Compounds for the Treatment of Hepatitis C

ABSTRACT

The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and may be useful in treating those infected with HCV.

CROSS REFERENCE TO RELATED APPLICATIONS

This continuation application claims the benefit of U.S. Ser. No.13/371,786 filed Feb. 13, 2012, now allowed, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.13/166,926 filed Jun. 23, 2011, now U.S. Pat. No. 8,148,382, which inturn is a continuation application which claims the benefit of U.S. Ser.No. 12/721,423 filed Mar. 10, 2010, now U.S. Pat. No. 7,994,171 which inturn is a continuation-in-part application which claims the benefit ofU.S. Ser. No. 12/554,193 filed Sep. 4, 2009, now U.S. Pat. No.8,048,887, which in turn claims the benefit of U.S. ProvisionalApplication Ser. No. 61/096,005 filed Sep. 11, 2008, now expired.

BACKGROUND OF THE INVENTION

The disclosure generally relates to the novel compounds of formula I,including their salts, which have activity against hepatitis C virus(HCV) and are useful in treating those infected with HCV. The disclosurealso relates to compositions and methods of using these compounds.

Hepatitis C virus (HCV) is a major human pathogen, infecting anestimated 170 million persons worldwide—roughly five times the numberinfected by human immunodeficiency virus type 1. A substantial fractionof these HCV infected individuals develop serious progressive liverdisease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.;Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the5′-untranslated region, HCV has been classified as a separate genus inthe Flaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome. At least six majorgenotypes have been characterized, and more than 50 subtypes have beendescribed. The major genotypes of HCV differ in their distributionworldwide, and the clinical significance of the genetic heterogeneity ofHCV remains elusive despite numerous studies of the possible effect ofgenotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to as NS3 protease) and mediatesall the subsequent cleavages downstream of NS3, both in cis, at theNS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions, acting as a cofactor for the NS3 protease and possiblyassisting in the membrane localization of NS3 and other viral replicasecomponents. The complex formation of the NS3 protein with NS4A seemsnecessary to the processing events, enhancing the proteolytic efficiencyat all of the sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. NS5B (also referred to asHCV polymerase) is a RNA-dependent RNA polymerase that is involved inthe replication of HCV. The HCV NS5B protein is described in “StructuralAnalysis of the Hepatitis C Virus RNA Polymerase in Complex withRibonucleotides (Bressanelli; S. et al., Journal of Virology 2002,3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7,211-242.

Currently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recentclinical results demonstrate that pegylated alpha-interferon is superiorto unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N.Engl. J. Med. 2000, 343, 1666-1672). However, even with experimentaltherapeutic regimens involving combinations of pegylatedalpha-interferon and ribavirin, a substantial fraction of patients donot have a sustained reduction in viral load. Thus, there is a clear andimportant need to develop effective therapeutics for treatment of HCVinfection.

HCV-796, an HCV NS5B inhibitor, showed an ability to reduce HCV RNAlevels in patients. The viral RNA levels decreased transiently and thenrebounded during dosing when treatment was with the compound as a singleagent but levels dropped more robustly when combined with the standardof care which is a form of interferon and ribavirin. The development ofthis compound was suspended due to hepatic toxicity observed duringextended dosing of the combination regimens. U.S. Pat. No. 7,265,152 andthe corresponding PCT patent application WO2004/041201A2 describecompounds of the HCV-796 class.

The invention provides technical advantages, for example, the compoundsare novel and are effective against hepatitis C. Additionally, thecompounds provide advantages for pharmaceutical uses, for example, withregard to one or more of their mechanism of action, binding, inhibitionefficacy, target selectivity, solubility, safety profiles, orbioavailability.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I

R¹ is R⁵R⁶N; alkoxy; (alkoxycarbonylamino)alkoxy; (alkylphenyl)alkoxy;(carboxy)alkenyl; (alkoxycarbonyl)alkenyl; (benzyloxycarbonyl)alkenyl;((N-dimethylbenzyl)aminocarbonyl)alkenyl; or phenyl where said phenyl issubstituted with 1-2 substituents selected from the group consisting ofhalo, cyano, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,(carboxy)alkyl, alkoxy, hydroxyalkyloxy, alkoxyalkyloxy, benzyloxy,tetrahydropyranyloxy, carboxy, alkoxycarbonyl, alkylsulfonyl,(carboxy)alkenyl, (alkoxycarbonyl)alkenyl, alkylcarboxamido,alkoxycarboxamido, alkylsulfamido, (alkylsulfamido)alkyl, Ar⁵,SO₂NR¹⁵R¹⁶, and CONR⁷R⁸; and where said phenyl is also substituted with0-2 substituents selected from the group consisting of halo; nitro;alkyl; cycloalkyl; haloalkyl; aminoalkyl; hydroxyalkyl; alkoxyalkyl;hydroxy; alkoxy; OR¹⁷; cycloalkoxy; amino; alkylamino; dialkylamino;alkylcarboxamido; alkoxycarboxamido; alkoxyalkylcarboxamido; furanyl,thienyl, or pyrazolyl substituted with 0-2 alkyl substituents; pyridinylsubstituted with 0-2 halo, cyano, alkyl, hydroxy, alkoxy, amino, oralkylaminocarbonyl substituents; pyrimidinyl; pyrimidinedionyl;aminopyrimidinyl; indolyl; isoquinolinyl; or phenyl substituted with 0-2substituents selected from halo, alkyl, cyanoalkyl, hydroxyalkyl,alkoxyalkyl, hydroxy, alkoxy, amino, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylcarboxamido, carboxyalkenyl, and phenyl;R² is hydrogen, halo, nitro, amino, phenyl, or R⁵R⁶N;R³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl,(alkylsulfonyl)aminocarbonyl, CONR¹¹R¹², (R¹¹)(R¹²)NCONH, triazolyl,thiazolyl, or tetrazolyl;R⁴ is phenyl substituted with 0-2 halo substituents;R⁵ is hydrogen, alkyl, or alkylsulfonyl;R⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl;R⁷ is hydrogen, alkyl, alkenyl, alkynyl, cyanoalkyl, haloalkyl,hydroxyalkyl, dihydroxyalkyl, alkoxyalkyl, oxoalkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkyl)alkyl, cycloalkyl,(alkyl)cycloalkyl, (hydroxyalkyl)cycloalkyl, (tetrahydrofuranyl)alkyl,(tetrahydropyranyl)alkyl, (carboxy)alkyl, (alkoxycarbonyl)alkyl,(alkenyloxycarbonyl)alkyl, (alkoxycarbonyl)hydroxyalkyl,(CONR¹³R¹⁴)alkyl, (CONR¹³R¹⁴)(hydroxyalkyl)alkyl, (CONR¹³R¹⁴)cylcoalkyl,(alkylcarbonyl)aminoalkyl, (phenyl)alkyl, (pyridinyl)alkyl,alkylsulfonyl, phenylsulfonyl, Ar², Ar³,

R⁸ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;or R⁷R⁸N taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, dihydroindolyl, or isoindolinyl, and issubstituted with 0-2 substituents selected from alkyl, hydroxyalkyl,alkoxyalkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl,dialkylcarboxamido, alkylcarbonylamino, alkoxycarbonylamino, pyridinyl,and phenyl where said phenyl is substituted with 0-2 halo or alkylsubstituents;or where R⁷R⁸N taken together is

(quinuclidinyl)amino, (quinuclidinyl)(alkyl)amino,(methylpyrrolidinyl)(alkyl)amino,((imidazolyl)alkyl)(hydroxyalkyl)amino, (alkylthiazolyl)amino,((carboxamido)cyclopentanyl)amino, ((halophenyl)cyclopentanyl)amino,3H-spiro(isobenzofuranyl)piperidinyl, (hydroxyindanyl)amino, or

R⁹ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;R¹⁰ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;or R⁹ and R¹⁰ taken together is ethylene, propylene, butylene,pentylene, or hexylene;R¹¹ is hydrogen, alkyl, or cycloalkyl;R¹² is hydrogen, alkyl, or cycloalkyl;or R¹¹ and R¹² taken together with the nitrogen to which they areattached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl;R¹³ is hydrogen, alkyl, cyanoalkyl, haloalkyl, alkenyl, alkynyl, orthiazolyl;R¹⁴ is hydrogen or alkyl;R¹⁵ is hydrogen, alkyl, hydroxyalkyl, cycloalkyl, or benzyl;R¹⁶ is hydrogen or alkyl;or R¹⁵ and R¹⁶ taken together with the nitrogen to which they areattached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl;R¹⁷ is haloalkyl, cyanoalkyl, (cycloalkyl)alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, (R¹⁸)alkyl, (Ar⁴)alkyl, alkynyl, oraminocycloalkyl;R¹⁸ is CONH₂, H₂NCONH, dibenzylamino, phthalimido, amino, alkylamino,dialkylamino, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl where azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl is substituted with 0-3 alkyl or alkoxycarbonylsubstituents;R¹⁹ is cyano, hydroxyalkyl, morpholinylalkyl, carboxy, alkoxycarbonyl,cycloalkylsulfoxamido, ((alkyl)pyrazolyl)amino,((alkyl)isoxazolyl)amino, (thiadiazolyl)amino, (triazinyl)amino, oralkynylaminocarbonyl;R²⁰ is hydrogen, halo, alkyl, or alkoxy;R²¹ is hydrogen, halo, alkyl, or alkoxy;Ar¹ is phenyl, naphthalenyl, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl,oxadiazolyl, oxadiathiazolyl, triazolyl, tetrazolyl, pyrazinyl,pyrimidinyl, or benzothiazolyl, and is substituted with 0-2 substituentsselected from halo, alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, hydroxy,alkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, pyridinyl,phenyl, halophenyl, alkylphenyl, and alkoxyphenyl;Ar² is phenyl, biphenyl, or pyridinyl and is substituted with 0-2substituents selected from halo, alkyl, cyano, hydroxy, alkoxy, andcarboxy;Ar³ is pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl,thiazolyl, triazolyl, oxadiazolyl, oxathiadiazolyl, pyrimidinyl, orpyrizinyl and is substituted with 0-2 substituents selected fromhydroxy, alkyl, hydroxyalkyl, and CONR¹³R¹⁴;Ar⁴ is furanyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, indolyl, orphenyl and is substituted with 0-2 substituents selected from halo,alkyl, haloalkyl, hydroxyl, and alkoxy; andAr⁵ is pyrrozolyl, imidazolyl, or oxadiazolyl and is substituted with0-2 substituents selected from alkyl, carboxy, alkoxycarbonyl, benzyl,and phenyl;or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R²⁰ andR²¹ are hydrogen.

Another aspect of the invention is a compound of formula I where

R¹ is R⁵R⁶N; (carboxy)alkenyl; (alkoxycarbonyl)alkenyl;(benzyloxycarbonyl)alkenyl; or phenyl where said phenyl is substitutedwith 1-2 substituents selected from the group consisting of cyano,alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxyalkyloxy,alkoxyalkyloxy, haloalkyl, benzyloxy, carboxy, alkoxycarbonyl,alkylsulfonyl, (carboxy)alkenyl, (alkoxycarbonyl)alkenyl,alkylcarboxamido, alkoxycarboxamido, alkylsulfamido,(alkylsulfamido)alkyl, tetrahydropyranyloxy, Ar⁵, SO₂NR¹⁵R¹⁶, andCONR⁷R⁸; and where said phenyl is also substituted with 0-1 substituentsselected from the group consisting of halo; alkyl; hydroxyalkyl;alkoxyalkyl; hydroxyl; alkoxy; OR¹⁷; cycloalkoxy; amino; alkylamino;dialkylamino; alkylcarboxamido; alkoxyalkylcarboxamido; furanyl;indolyl; isoquinolinyl; pyridinyl substituted with 0-2 halo, alkyl,hydroxy, or alkoxy substituents; pyrazolyl substituted with 0-2 alkylsubstituents; and phenyl substituted with 0-2 halo, alkyl, cyanoalkyl,hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, carboxy, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylcarboxamido, carboxyalkenyl, or phenyl substituents;R² is hydrogen, nitro, or R⁵R⁶N;R³ is cyano, alkoxycarbonyl, (cycloalkyl)oxycarbonyl,(alkylsulfonyl)aminocarbonyl, CONR¹¹R¹², (R¹¹)(R¹²)NCONH, triazolyl,thiazolyl, or tetrazolyl;R⁴ is phenyl substituted with 0-2 halo substituents;R⁵ is hydrogen, alkyl, or alkylsulfonyl;R⁶ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or alkylsulfonyl;R⁷ is hydrogen, alkyl, alkenyl, alkynyl, cyanoalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, oxoalkyl, aminoalkyl, (alkylamino)alkyl,(dialkylamino)alkyl, (cycloalkyl)alkyl, cycloalkyl, (alkyl)cycloalkyl,(hydroxyalkyl)cycloalkyl, (tetrahydrofuranyl)alkyl,(tetrahydropyranyl)alkyl, (carboxy)alkyl, (alkoxycarbonyl)alkyl,(alkoxycarbonyl)hydroxyalkyl, (CONR¹³R¹⁴)alkyl,(alkylcarbonyl)aminoalkyl, (phenyl)alkyl, (pyridinyl)alkyl,alkylsulfonyl, phenylsulfonyl, Ar², Ar³,

R⁸ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;or R⁷R⁸N taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or dihydroindolyl, and is substituted with 0-2substituents selected from alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy,alkoxy, carboxy, alkoxycarbonyl, dimethylcarboxamido,alkylcarbonylamino, alkoxycarbonylamino, pyridinyl, and phenyl wherephenyl is substituted with 0-2 substituents selected from halo andalkyl;or where R⁷R⁸N taken together is

(quinuclidinyl)(alkyl)amino, (methylpyrrolidinyl)(alkyl)amino,(alkylthiazolyl)amino, ((carboxamido)cyclopentanyl)amino,((halophenyl)cyclopentanyl)amino, or (hydroxyindanyl)amino;R⁹ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;R¹⁰ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;or R⁹ and R¹⁰ taken together is ethylene, propylene, butylene, orpentylene;R¹¹ is hydrogen, alkyl, or cycloalkyl;R¹² is hydrogen, alkyl, or cycloalkyl;or R¹¹ and R¹² taken together with the nitrogen to which they areattached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl;R¹³ is hydrogen, alkyl, cyanoalkyl, alkenyl, or alkynyl;R¹⁴ is hydrogen or alkyl;R¹⁵ is hydrogen or alkyl;R¹⁶ is hydrogen or alkyl;R¹⁷ is haloalkyl, hydroxyalkyl, alkoxyalkyl, alkynyl, (R¹⁸)alkyl or(Ar⁴)alkyl;R¹⁸ is CONH₂, dibenzylamino, amino, alkylamino, dialkylamino,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl whereazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, andis substituted with 0-3 substituents selected from alkyl andalkoxycarbonyl;R¹⁹ is cyano, ((alkyl)pyrazolyl)amino, ((alkyl)isoxazolyl)amino(thiadiazolyl)amino, or (triazinyl)amino;R²⁰ and R²¹ are hydrogen;Ar¹ is phenyl, naphthalenyl, pyridinyl, thienyl, thiazolyl, or pyrazinyland is substituted with 0-2 substituents selected from alkyl, halo,hydroxy, alkoxy, amino, alkylamino, and dialkylamino;Ar² is phenyl, biphenyl, or pyridinyl and is substituted with 0-2substituents selected from halo, alkyl, cyano, hydroxy, and alkoxy;Ar³ is pyrazolyl isoxazolyl, thiazolyl, pyrimidinyl, or pyrizinyl and issubstituted with 0-2 substituents selected from alkyl and hydroxyalkyl;

Ar⁴ is pyrrolyl, imidazolyl, pyridinyl, indolyl, or phenyl and issubstituted with 0-2 substituents selected from halo, alkyl, hydroxyl,and alkoxy; and

Ar⁵ is pyrrozolyl, imidazolyl, or oxadiazolyl and is substituted with0-2 substituents selected from alkyl, carboxy, alkoxycarbonyl, benzyl,and phenyl;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ isalkoxy; (alkoxycarbonylamino)alkoxy; (alkylphenyl)alkoxy;(carboxy)alkenyl; ((N-dimethylbenzyl)aminocarbonyl)alkenyl; or phenylwhere said phenyl is substituted with 1-2 substituents selected from thegroup consisting of halo, cyano, alkyl, haloalkyl, hydroxyalkyl,(carboxy)alkyl, alkoxy, hydroxyalkyloxy, tetrahydropyranyloxy, carboxy,alkoxycarbonyl, (carboxy)alkenyl, alkylcarboxamido, alkoxycarboxamido,(alkylsulfamido)alkyl, Ar⁵, SO₂NR¹⁵R¹⁶, and CONR⁷R⁸; and where saidphenyl is also substituted with 0-2 substituents selected from the groupconsisting of halo; nitro; alkyl; cycloalkyl; haloalkyl; aminoalkyl;hydroxy; alkoxy; OR¹⁷; cycloalkoxy; amino; alkoxycarboxamido; furanyl,thienyl, or pyrazolyl substituted with 0-2 alkyl substituents; pyridinylsubstituted with 0-2 halo, cyano, alkyl, hydroxy, alkoxy, amino, oralkylaminocarbonyl substituents; pyrimidinyl; pyrimidinedionyl;aminopyrimidinyl; indolyl; isoquinolinyl; and phenyl substituted with0-2 substituents selected from halo, cyanoalkyl, hydroxyalkyl,alkoxyalkyl, alkoxy, amino, carboxy, aminocarbonyl, alkylaminocarbonyl,alkylcarboxamido, and carboxyalkenyl;

R² is hydrogen, halo, nitro, amino, phenyl, or R⁵R⁶N;

R³ is CONR¹¹R¹²;

R⁴ is phenyl substituted with 0-2 halo substituents;R⁵ is hydrogen or alkylsulfonyl;R⁶ is hydrogen, alkyl, hydroxyalkyl, or alkylsulfonyl;R⁷ is hydrogen, alkyl, alkynyl, cyanoalkyl, haloalkyl, hydroxyalkyl,dihydroxyalkyl, alkoxyalkyl, oxoalkyl, (dialkylamino)alkyl,(cycloalkyl)alkyl, cycloalkyl, (alkyl)cycloalkyl,(hydroxyalkyl)cycloalkyl, (tetrahydrofuranyl)alkyl,(tetrahydropyranyl)alkyl, (carboxy)alkyl, (alkoxycarbonyl)alkyl,(alkenyloxycarbonyl)alkyl, (alkoxycarbonyl)hydroxyalkyl,(CONR¹³R¹⁴)alkyl, (CONR¹³R¹⁴)(hydroxyalkyl)alkyl, (CONR¹³R¹⁴)cylcoalkyl,(alkylcarbonyl)aminoalkyl, (phenyl)alkyl, alkylsulfonyl, phenylsulfonyl,Ar², Ar³,

R⁸ is hydrogen, alkyl, or alkoxyalkyl;or R⁷R⁸N taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, dihydroindolyl, or isoindolinyl, and issubstituted with 0-2 substituents selected from alkyl, hydroxyalkyl,alkoxyalkyl, hydroxy, alkoxycarbonyl, dialkylcarboxamido,alkylcarbonylamino, pyridinyl, and phenyl where said phenyl issubstituted with 0-2 halo or alkyl substituents;or where R⁷R⁸N taken together is

(quinuclidinyl)amino, (quinuclidinyl)(alkyl)amino,(methylpyrrolidinyl)(alkyl)amino,((imidazolyl)alkyl)(hydroxyalkyl)amino, (alkylthiazolyl)amino,((carboxamido)cyclopentanyl)amino, ((halophenyl)cyclopentanyl)amino,3H-spiro(isobenzofuranyl)piperidinyl, (hydroxyindanyl)amino, or

R⁹ is hydrogen, alkyl, or hydroxyalkyl;R¹⁰ is hydrogen or alkyl;or R⁹ and R¹⁰ taken together is ethylene or propylene;R¹¹ is alkyl;R¹² is hydrogen;R¹³ is hydrogen, alkyl, cyanoalkyl, haloalkyl, alkenyl, or thiazolyl;R¹⁴ is hydrogen or alkyl;R¹⁵ is alkyl, hydroxyalkyl, cycloalkyl, or benzyl;R¹⁶ is hydrogen;or R¹⁵ and R¹⁶ taken together with the nitrogen to which they areattached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl;R¹² is haloalkyl, cyanoalkyl, (cycloalkyl)alkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, (R¹⁸)alkyl, (Ar⁴)alkyl, alkynyl, oraminocycloalkyl;R¹⁸ is CONH₂, H₂NCONH, dibenzylamino, phthalimido, amino, dialkylamino,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl where azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is substitutedwith 0-3 alkyl or alkoxycarbonyl substituents;R¹⁹ is cyano, hydroxyalkyl, morpholinylalkyl, carboxy, alkoxycarbonyl,cycloalkylsulfoxamido, ((alkyl)pyrazolyl)amino,((alkyl)isoxazolyl)amino, (thiadiazolyl)amino, (triazinyl)amino, oralkynylaminocarbonyl;R²⁰ and R²¹ are hydrogen;Ar¹ is phenyl, naphthalenyl, pyridinyl, furanyl, pyrazolyl, isoxazolyl,imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl,pyrazinyl, pyrimidinyl, or benzothiazolyl, and is substituted with 0-2substituents selected from halo, alkyl, cycloalkyl, haloalkyl,alkoxyalkyl, hydroxy, alkoxy, amino, aminocarbonyl, pyridinyl, phenyl,halophenyl, alkylphenyl, and alkoxyphenyl;Ar² is phenyl, biphenyl, or pyridinyl and is substituted with 0-2substituents selected from halo, alkyl, cyano, hydroxy, alkoxy, andcarboxy;Ar³ is pyrazolyl, isoxazolyl, thiazolyl, triazolyl, pyrimidinyl, orpyrizinyl and is substituted with 0-2 substituents selected fromhydroxy, alkyl, and CONR¹³R¹⁴;Ar⁴ is furanyl, pyrrolyl, pyrazolyl, isoxazolyl, imidazolyl,oxadiazolyl, triazolyl, pyridinyl, indolyl, or phenyl and is substitutedwith 0-2 substituents selected from halo, alkyl, haloalkyl, and hydroxy;andAr⁵ is pyrrozolyl, imidazolyl, or oxadiazolyl and is substituted with0-2 substituents selected from alkyl, alkoxycarbonyl, benzyl, andphenyl;or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ isphenyl substituted with 1 CONR⁷R⁸ substituent and also substituted with0-2 halo, alkyl, or alkoxy substituents; R² is hydrogen, halo, or R⁵R⁶N;R³CONR¹¹R¹²; R⁴ is monofluorophenyl; R⁵ is alkylsulfonyl; R⁶ ishydroxyalkyl; R⁷ is

R⁸ is hydrogen; R⁹ is alkyl; R¹⁶ is alkyl or R⁹ and R¹⁶ taken togetheris ethylene or propylene; R¹¹ is alkyl; R¹² is hydrogen; R²⁰ and R²¹ arehydrogen; Ar¹ is phenyl, pyridinyl, pyrimidinyl, isoxazolyl, oxazolyl,or oxadiazolyl, and is substituted with 0-1 halo or alkyl substituents;or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ isphenyl substituted with 1-2 substituents selected from the groupconsisting of halo, cyano, alkyl, haloalkyl, hydroxyalkyl,(carboxy)alkyl, alkoxy, hydroxyalkyloxy, tetrahydropyranyloxy, carboxy,alkoxycarbonyl, (carboxy)alkenyl, alkylcarboxamido, alkoxycarboxamido,(alkylsulfamido)alkyl, Ar⁵, SO₂NR¹⁵R¹⁶, and CONR⁷R⁸; and where saidphenyl is also substituted with 0-2 substituents selected from the groupconsisting of halo; nitro; alkyl; cycloalkyl; haloalkyl; aminoalkyl;hydroxy; alkoxy; OR¹⁷; cycloalkoxy; amino; alkoxycarboxamido; furanyl,thienyl, or pyrazolyl substituted with 0-2 alkyl substituents; pyridinylsubstituted with 0-2 halo, cyano, alkyl, hydroxy, alkoxy, amino, oralkylaminocarbonyl substituents; pyrimidinyl; pyrimidinedionyl;aminopyrimidinyl; indolyl; isoquinolinyl; and phenyl substituted with0-2 substituents selected from halo, cyanoalkyl, hydroxyalkyl,alkoxyalkyl, alkoxy, amino, carboxy, aminocarbonyl, alkylaminocarbonyl,alkylcarboxamido, and carboxyalkenyl.

Another aspect of the invention is a compound of formula I where R¹ isphenyl substituted with 1 CONR⁷R⁸ substituent and also substituted with0-2 halo, alkyl, or alkoxy substituents.

Another aspect of the invention is compound of formula I where R⁷ is

and at least one of R⁹ and R¹⁰ is not hydrogen.

Another aspect of the invention is compound of formula I where R² isR⁵R⁶N.

Another aspect of the invention is compound of formula I where R³ isCONR¹¹R¹².

Another aspect of the invention is compound of formula I where R⁴ isphenyl or monofluorophenyl.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Cycloalkyl” means amonocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,”“alkoxy” and other terms with a substituted alkyl moiety includestraight and branched isomers composed of 1 to 6 carbon atoms for thealkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo substituted alkyl to perhalo substituted alkyl.“Aryl” includes carbocyclic and heterocyclic aromatic substituents.Parenthetic and multiparenthetic terms are intended to clarify bondingrelationships to those skilled in the art. For example, a term such as((R)alkyl) means an alkyl substituent further substituted with thesubstituent R.

Substituents which are illustrated by chemical drawing to bond atvariable positions on a multiple ring system (for example a bicyclicring system) are intended to bond to the ring where they are drawn toappend. For example, substituents R¹ and R² of formula I are intended tobond to the benzene ring of formula I and not to the furan ring.

Ethylene means ethanediyl or —CH₂CH₂—; propylene means propanediyl or—CH₂CH₂CH₂—; butylene means butanediyl or —CH₂CH₂CH₂CH₂—; pentylenemeans pentanediyl or —CH₂CH₂CH₂CH₂CH₂—.

Dioxothiazinyl means

Any scope of any variable including R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, Ar¹, Ar²,Ar³, Ar⁴, or Ar⁵ can be used independently with the scope of any otherinstance of a variable.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms.The invention includes all stereoisomeric forms, including enantiomersand diastereomers as well as mixtures of stereoisomers such asracemates. Some stereoisomers can be made using methods known in theart. Stereoisomeric mixtures of the compounds and related intermediatescan be separated into individual isomers according to methods known inthe art.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Synthetic Methods

The compounds may be made by methods known in the art including thosedescribed below and including variations within the skill of the art.Some reagents and intermediates are known in the art. Other reagents andintermediates can be made by methods known in the art using readilyavailable materials. The variables (e.g. numbered “R” substituents) usedto describe the synthesis of the compounds are intended only toillustrate how to make the compounds and are not to be confused withvariables used in the claims or in other sections of the specification.The following methods are for illustrative purposes and are not intendedto limit the scope of the invention.

Abbreviations used in the schemes generally follow conventions used inthe art. Chemical abbreviations used in the specification and examplesare defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amide;“DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” forN-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “LAH”for lithium aluminum hydride; “BOC”, “DMSO” for dimethylsulfoxide; “h”for hours; “rt” for room temperature or retention time (context willdictate); “min” for minutes; “EtOAc” for ethyl acetate; “THF” fortetrahydrofuran; “EDTA” for ethylenediaminetetraacetic acid; “Et₂O” fordiethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for1,2-dichloroethane; “ACN” for acetonitrile; “DME” for1,2-dimethoxyethane; “HOBt” for 1-hydroxybenzotriazole hydrate; “DIEA”for diisopropylethylamine, “Nf” for CF₃(CF₂)₃SO₂—; and “TMOF” fortrimethylorthoformate.

As shown in Scheme 1, some compounds of the invention may be prepared bycoupling a benzofuran triflate or halide to a substituted phenyl boronicacid that in some examples contains a carboxylic acid or carboxylic acidester. Other coupling techniques and conditions are also known in theart as are other carbon-carbon bond forming reactions. Acids and estersmay be converted to amides by methods known in the art.

Scheme 2 depicts one specific example of Scheme 1.

As shown in Scheme 2, a nitro group on the benzofuran ring may bereduced and the resulting amino group may be functionalized using knownchemistry. For example, the amine may be converted to a monosulfonamidevia reaction with a sulfonyl chloride or by preparation of a bissulfonamide followed by selective hydrolysis. The monosulfonamide may bealkylated again with either a simple or functionalized alkyl. In Scheme3, the hydroxyl ethyl group is unmasked via acidic removal of the silylprotecting group.

Scheme 3 depicts the preparation of two intermediates labelled as commonintermediate 1 and 2 which can be used to prepare some compounds of theinvention. The isopropyl group is used to temporarily mask the C5hydroxy group so the methyl amide can be constructed from the ethylester. The more advanced common intermediate 2 allows functionalizationof the sulfonamide, acid deprotection and formation of some amidecompounds after coupling of amines to the acid as described earlier.

Scheme 4 depicts some conditions for preparing some of the compoundsdescribed and for accessing an alternate common intermediate 3 whichallows amide formation prior to nitro reduction and aminefunctionalization.

Scheme 5 illustrates a method for preparing some compounds by preparing2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamidein which the boron is attached to the benozfuran and then coupling totriflates or halogen containing aryl moieties.

Scheme 6 shows a preparation of the functionalized benzofuran and Scheme7 shows one method for installation of nitrogen functionality which canthen functionalized as described in the previous schemes.

Scheme 8 illustrates that a free phenolic OH group can be used to formsome ether compounds. Scheme 9 provides an alkylation for forming ethersunder mild or more extreme conditions depending on the reactivity of thealkylating reagent.

Scheme 10 shows how an ether with a protected amine can be attached, andafter subsequent deprotection of the pthalimide, a free amine isliberated which can be either incorporated into compounds of theinvention or derivatized further via standard chemistry to providesecondary or tertiary amines or amides or sulfonamides.

The compounds demonstrated activity against HCV NS5B as determined inthe following HCV RdRp assays.

HCV NS5B RdRp Cloning, Expression, and Purification.

The cDNA encoding the NS5B protein of HCV, genotype 1b, was cloned intothe pET21a expression vector. The protein was expressed with an 18 aminoacid C-terminal truncation to enhance the solubility. The E. colicompetent cell line BL21(DE3) was used for expression of the protein.Cultures were grown at 37° C. for ˜4 hours until the cultures reached anoptical density of 2.0 at 600 nm. The cultures were cooled to 20° C. andinduced with 1 mM IPTG. Fresh ampicillin was added to a finalconcentration of 50 μg/ml and the cells were grown overnight at 20° C.

Cell pellets (3 L) were lysed for purification to yield 15-24 mgs ofpurified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500mM NaCl, 0.5% triton X-100, 1 mM DTT, 1 mM EDTA, 20% glycerol, 0.5 mg/mllysozyme, 10 mM MgCl₂, 15 ug/ml deoxyribonuclease I, and Complete TMprotease inhibitor tablets (Roche). After addition of the lysis buffer,frozen cell pellets were resuspended using a tissue homogenizer. Toreduce the viscosity of the sample, aliquots of the lysate weresonicated on ice using a microtip attached to a Branson sonicator. Thesonicated lysate was centrifuged at 100,000×g for 1 hr at 4° C. andfiltered through a 0.2 μm filter unit (Corning).

The protein was purified using three sequential chromatography steps:Heparin sepharose CL-6B, polyU sepharose 4B, and Hitrap SP sepharose(Pharmacia). The chromatography buffers were identical to the lysisbuffer but contained no lysozyme, deoxyribonuclease I, MgCl2 or proteaseinhibitor and the NaCl concentration of the buffer was adjustedaccording to the requirements for charging the protein onto the column.Each column was eluted with a NaCl gradient which varied in length from5-50 column volumes depending on the column type. After the finalchromatography step, the resulting purity of the enzyme is >90% based onSDS-PAGE analysis. The enzyme was aliquoted and stored at −80° C.

Standard HCV NS5B RdRp Enzyme Assay.

HCV RdRp genotype 1b assays were run in a final volume of 60 μl in 96well plates (Costar 3912). The assay buffer is composed of 20 mM Hepes,pH 7.5, 2.5 mM KCl, 2.5 mM MgCl2, 1 mM DTT, 1.6 U RNAse inhibitor(Promega N2515), 0.1 mg/ml BSA (Promega R3961), and 2% glycerol. Allcompounds were serially diluted (3-fold) in DMSO and diluted further inwater such that the final concentration of DMSO in the assay was 2%. HCVRdRp genotype 1b enzyme was used at a final concentration of 28 nM. ApolyA template was used at 6 nM, and a biotinylated oligo-dT12 primerwas used at 180 nM final concentration. Template was obtainedcommercially (Amersham 27-4110). Biotinylated primer was prepared bySigma Genosys. 3H-UTP was used at 0.6 μCi (0.29 μM total UTP). Reactionswere initiated by the addition of enzyme, incubated at 30° C. for 60min, and stopped by adding 25 μl of 50 mM EDTA containing SPA beads (4μg/μl, Amersham RPNQ 0007). Plates were read on a Packard Top Count NXTafter >1 hr incubation at room temperature.

Modified HCV NS5B RdRp Enzyme Assay.

A modified enzyme assay was performed essentially as described for thestandard enzyme assay except for the following: The biotinylated oligodT12 primer was precaptured on streptavidin-coated SPA beads by mixingprimer and beads in assay buffer and incubating at room temperature forone hour. Unbound primer was removed after centrifugation. Theprimer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 andused in the assay at final concentrations of 20 nM primer and 0.67 μg/μlbeads. Order of addition in the assay: enzyme (14 nM) was added todiluted compound followed by the addition of a mixture of template (0.2nM), 3H-UTP (0.6 μCi, 0.29 μM), and primer-bound beads, to initiate thereaction; concentrations given are final. Reactions were allowed toproceed for 4 hours at 30° C.

IC₅₀ values for compounds were determined using seven different [I].IC₅₀ values were calculated from the inhibition using the formulay=A+((B−A)/(1+((C/x)̂D))).

FRET Assay Preparation.

To perform the HCV FRET screening assay, 96-well cell culture plateswere used. The FRET peptide (Anaspec, Inc.) (Taliani et al., Anal.Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, nearone end of the peptide and an acceptor, DABCYL, near the other end. Thefluorescence of the peptide is quenched by intermolecular resonanceenergy transfer (RET) between the donor and the acceptor, but as the NS3protease cleaves the peptide the products are released from RETquenching and the fluorescence of the donor becomes apparent. The assayreagent was made as follows: 5× cell Luciferase cell culture lysisreagent from Promega (#E153A) diluted to 1× with dH₂O, NaCl added to 150mM final, the FRET peptide diluted to 20 μM final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renillaluciferase reporter gene, were trypsinized and placed into each well ofa 96-well plate with titrated test compounds added in columns 3 through12; columns 1 and 2 contained a control compound (HCV proteaseinhibitor), and the bottom row contained cells without compound. Theplates were then placed in a CO₂ incubator at 37° C.

Assays.

Subsequent to addition of the test compounds described above (FRET AssayPreparation), at various times the plate was removed and Alamar bluesolution (Trek Diagnostics, #00-100) was added per well as a measure ofcellular toxicity. After reading in a Cytoflour 4000 instrument (PEBiosystems), plates were rinsed with PBS and then used for FRET assay bythe addition of 30 ul of the FRET peptide assay reagent described above(FRET Assay Preparation) per well. The plate was then placed into theCytoflour 4000 instrument which had been set to 340 excite/490 emission,automatic mode for 20 cycles and the plate read in a kinetic mode.Typically, the signal to noise using an endpoint analysis after thereads was at least three-fold. Alternatively, after Alamar blue reading,plates were rinsed with PBS, 50 ul of DMEM (high glucose) without phenolred was added and plates were then used for luciferase assay using thePromega Dual-Glo Luciferase Assay System.

Compound analysis was determined by quantification of the relative HCVreplicon inhibition and the relative cytotoxicity values. To calculatecytoxicity values, the average Alamar Blue fluorescence signals from thecontrol wells were set as 100% non-toxic. The individual signals in eachof the compound test wells were then divided by the average controlsignal and multiplied by 100% to determine percent cytotoxicity. Tocalculate the HCV replicon inhibition values, an average backgroundvalue was obtained from the two wells containing the highest amount ofHCV protease inhibitor at the end of the assay period. These numberswere similar to those obtained from naïve Huh-7 cells.

The background numbers were then subtracted from the average signalobtained from the control wells and this number was used as 100%activity. The individual signals in each of the compound test wells werethen divided by the averaged control values after background subtractionand multiplied by 100% to determine percent activity. EC₅₀ values for aprotease inhibitor titration were calculated as the concentration whichcaused a 50% reduction in FRET or luciferase activity. The two numbersgenerated for the compound plate, percent cytoxicity and percentactivity were used to determine compounds of interest for furtheranalysis.

HCV Replicon Luciferase Reporter Assay

The HCV replicon luciferase assay was developed to monitor theinhibitory effects of compounds described in the disclosure on HCV viralreplication. Utilization of a replicon luciferase reporter assay wasfirst described by Krieger et al (Krieger N, Lohmann V, andBartenschlager R, J. Virol. 75(10):4614-4624 (2001)). HUH-7 cells,constitutively expressing the HCV replicon, were grown in Dulbecco'sModified Eagle Media (DMEM) (Gibco-BRL) containing 10% Fetal calf serum(FCS) (Sigma) and 1 mg/ml G418 (Gibco-BRL). Compounds were seriallydiluted 3 folds in DMSO for a twenty-point titration and subsequentlytransferred to sterile 384-well tissue-culture treated plates (Corningcat #3571). The plates were then seeded with 50 μl of cells at a densityof 3.0×10³ cells/well in DMEM containing 4% FCS (final DMSOconcentration at 0.5%). After 3 days incubation at 37° C., cells wereanalyzed for Renilla Luciferase activity using the EnduRen as substrate(Promega cat #E6485). The EnduRen substrate was diluted in DMEM and thenadded to the plates to a final concentration of 7.5 μM. The plates wereincubated for 2 hrs at 37° C. and then read immediately for 30 secondswith Viewlux Imager (PerkinElmer) using a luminescence program. Toassess cytotoxicity of compounds, CC₅₀ values were generated bymultiplexing the EnduRen-containing plates with Cell Titer-Blue(Promega, cat #G8082). 3 μl of Cell-Titer Blue was added to each welland incubated for 8 hrs at 37° C. The fluorescence signal from each wellwas read, with an excitation wavelength at 525/10 nm and an emissionwavelength of 598/10 nm, using the Viewlux Imager.

Representative data for compounds are reported in Tables 1a, 1b, 1c, 1d,and 1e.

TABLE 1a Structure IC₅₀ EC₅₀

A A

A A

A A

A A

A A

A A

A A

A A

B A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

B A

A A

B A

A A

A A

A A

A A

B A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

B A

A A

A A

A A

A A

A A

A A

F A

A A

A A

A A

A A

A A

B A

A A

A A

A A

B A

A A

A A

A A

A A

A A

A A

A A

A A

C A

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

E B

E F

E H

E F

E B

C B

B B

A A

B B

A B

B B

B B

B B

A B

A B

B B

B B

C B

A B

A B

B B

A B

B B

A B

A B

A B

C B

E B

A A

B B

B B

A B

B B

B B

B B

B B

A B

G B

C B

A B

B B

B B

B B

B B

A B

C B

E B

E B

B B

B B

B B

B B

A B

B B

B B

B B

G B

B B

C C

C

C

C C

B C

C C

C C

C C

E C

C C

E C

E C

E C

E C

E C

C C

E C

B C

C C

C C

C C

C C

B C

C C

B C

C C

B C

C C

C C

C C

B C

B C

B C

C C

C C

C C

C C

E C

C C

C C

B C

C C

B C

C C

B C

C C

C C

C C

C C

C C

E C

E C

E C

E C

E C

B C

C C

C C

C C

A C

C C

A C

B C

B C

C C

C C

B C

B C

B C

B C

B C

B C

C C

C C

F C

A C

A C

G C

C C

E C

E C

E J

E K

E J

E K

E K

E K

E K

E K

E H

C J

E J

E J

E J

C E

C E

E E

C E

E E

C E

C E

E E

E E

E E

C E

E E

C E

C E

E E

E E

C E

B E

C E

C E

E E

E E

E E

E E

C E

E E

E E

C E

C E

E E

E E

E E

E E

E E

E E

C E

C E

C E

B E

B E

C E

C E

B E

A E

C E

C E

B E

B E

A E

C E

A E

B E

B E

B E

E E

I E

E E

E E

E E

E E

C E

E E

F E

TABLE 1b Structure IC₅₀ EC₅₀

B A

A A

E C

C B

E C

A

A A

A A

A

A A

A

A A

B A

A A

E

A A

A B

C

B A

A

A A

A A

B C

A

B A

A A

A A

A

E B

G B

E A

A A

A A

A A

A A

B A

A A

C C

A A

A A

C E

A A

A A

A A

A A

A A

A A

A A

E E

B A

A A

A A

A A

B A

A A

A

A A

A A

A A

A A

C C

A A

A A

A A

A A

B B

C B

E E

A A

A A

A A

A A

A A

B A

B A

A A

E E

A A

C B

C C

B A

B B

A A

C

A

A

A

B

C

A A

A A

A A

A A

C C

A A

B B

A A

A A

A A

E C

A A

A B

A A

B B

C

A A

A

E E

A A

A B

A A

A A

C C

A A

C B

A A

A A

A A

A A

A C

C C

A A

A A

A A

A A

A C

A A

C E

A A

A A

A A

A A

E

E

A A

E E

A A

A A

A A

E E

A A

A E

A B

A A

A A

A

A A

A A

A A

C E

B E

A B

A A

E

B A

B A

A A

A A

A A

E B

A

A

B A

A A

A A

B B

E C

A A

A A

A A

L A

A

A A

A B

A

L A

B

A

B

A

A B

L A

B

B

A B

A C

A A

C C

A M

C C

E B

C C

C C

A C

E C

M C

M C

C C

C C

G C

C C

E C

A C

B C

A A

A A

A A

A A

A A

A A

A A

A A

A A

A A

B E

A

A

A A

A A

A

A A

A A

A A

A A

A A

A A

B A

A B

A

A A

A A

A

A A

A A

A

A

A

A A

A A

N A

A A

A A

A A

A A

A A

C

N A

A A

A A

A A

A

A A

N A

A A

A A

A A

A A

A A

C E

N A

B A

A A

A

A

A

A 0.002 or less to 0.25 μM; B>0.25 μM-<1.0 μM; C 1.0 μM-10.0 μM; D>0.67μM but an exact value was not determined; E>10.0 μM; F>0.4 μM; but anexact value was not determined; G>1.39 μM but an exact value was notdetermined; H>0.62 μM but an exact value was not determined; I>4 μM butan exact value was not determined; J>3.7 μM but an exact value was notdetermined; K>1.23 μM but an exact value was not determined; L<0.02 μMbut an exact value was not determined; M>0.50 but an exact value was notdetermined N<0.02 but an exact value was not determined

IC₅₀ EC₅₀ Structure (μM) (μM)

0.02 1.60E- 03*

<0.02  3.04E- 04*

0.01 4.25E- 04*

0.02 7.86E- 04*

7.20E-03 8.05E- 04*

3.95E-03 8.30E- 04*

9.95E-03 1.78E-03

0.01 1.83E-03

8.60E-03 1.95E-03

5.45E-03 2.47E-03

9.65E-03 3.04E-03

0.02 3.57E-03

5.90E-03 3.58E-03

0.29 1.13

>12.50  1.13

0.80 1.25

0.60 1.26

1.71 1.34

0.80 1.38

1.15 1.39

4.75 13.26 

>12.50  13.66 

9.92 15.11 

10.39  15.39 

7.13 16.08 

5.68E- 03* *EC50 determined using 384 well plate method

TABLE 1d Structure IC₅₀ EC₅₀

A A

N A

N A

N A

A A

N A

N A

A A

A A

A A

A

A A

N A

A

A

A

A

A

B

A A

A A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A A

A

A

A

A

A

A

A

A A

A A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A 0.001 to 0.25 μM; B>0.25 μM-<1.0 μM; C 1.0 μM-10.0 μM; D>0.67 μM butan exact value was not determined; E>10.0 μM; F>0.4 μM; but an exactvalue was not determined; G>1.39 μM but an exact value was notdetermined; H>0.62 μM but an exact value was not determined; I>4 μM butan exact value was not determined; J>3.7 μM but an exact value was notdetermined; K>1.23 μM but an exact value was not determined; L<0.02 μMbut an exact value was not determined; M>0.50 but an exact value was notdetermined N<0.02 but an exact value was not determined

TABLE 1d IC₅₀ EC₅₀ Structure (μM) (μM)

<0.017 0.0019

0.002

0.21

0.0021 0.001

0.0081 0.0024

0.002

0.010

0.056

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful intreating HCV and HCV infection. Therefore, another aspect of theinvention is a composition comprising a compound, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising acompound having anti-HCV activity.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is an interferon. Another aspect of theinvention is where the interferon is selected from interferon alpha 2B,pegylated interferon alpha, consensus interferon, interferon alpha 2A,and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is a cyclosporin. Another aspect of theinvention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is selected from the group consisting ofinterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from HCV metalloprotease, HCV serine protease, HCVpolymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCVegress, HCV NS5A protein, IMPDH, and a nucleoside analog for thetreatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound,or a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the functionof the HCV replicon comprising contacting the HCV replicon with acompound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the functionof the HCV NS5B protein comprising contacting the HCV NS5B protein witha compound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable saltthereof. Another aspect of the invention is a method of inhibiting thefunction of the HCV replicon. Another aspect of the invention is amethod of inhibiting the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable saltthereof, in conjunction with (prior to, after, or concurrently) anothercompound having anti-HCV activity.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin iscyclosporin A.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from the group consisting of HCV metalloprotease, HCVserine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and anucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of targetin the HCV life cycle other than the HCV NS5B protein.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of hepatitis and HCV infection.

“Patient” means a person infected with the HCV virus and suitable fortherapy as understood by practitioners in the field of hepatitis and HCVinfection.

“Treatment,” “therapy,” “regimen,” “HCV infection,” and related termsare used as understood by practitioners in the field of hepatitis andHCV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients.Pharmaceutically acceptable carriers are those conventionally knowncarriers having acceptable safety profiles. Compositions encompass allcommon solid and liquid forms including for example capsules, tablets,losenges, and powders as well as liquid suspensions, syrups, elixers,and solutions. Compositions are made using common formulationtechniques, and conventional excipients (such as binding and wettingagents) and vehicles (such as water and alcohols) are generally used forcompositions. See, for example, Remington's Pharmaceutical Sciences,Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regime,however, will be determined by a physician using sound medical judgment.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating hepatitis andHCV infection. In these combination methods, the compound will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regime, however, willbe determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods arelisted in Table 2.

TABLE 2 Type of Inhibitor or Brand Name Target Source Company Omega IFNIFN-ω Intarcia Therapeutics BILN-2061 serine protease BoehringerIngelheim inhibitor Pharma KG, Ingelheim, Germany Summetrel antiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA Roferon A IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys PEGylated IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and RibavirinPEGylated IFN- F. Hoffmann-La Roche α2a/ribavirin LTD, Basel,Switzerland CellCept HCV IgG F. Hoffmann-La Roche immunosuppressant LTD,Basel, Switzerland Wellferon lymphoblastoid IFN- GlaxoSmithKline plc,αn1 Uxbridge, UK Albuferon-α albumin IFN-α2b Human Genome Sciences Inc.,Rockville, MD Levovirin ribavirin ICN Pharmaceuticals, Costa Mesa, CAIDN-6556 caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CAIP-501 antifibrotic Indevus Pharmaceuticals Inc., Lexington, MAActimmune INF-γ InterMune Inc., Brisbane, CA Infergen A IFN alfacon-1InterMune Pharmaceuticals Inc., Brisbane, CA ISIS 14803 antisense ISISPharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NYJTK-003 RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Pegasys andCeplene PEGylated IFN-α2a/ Maxim Pharmaceuticals immune modulator Inc.,San Diego, CA Ceplene immune modulator Maxim Pharmaceuticals Inc., SanDiego, CA Civacir HCV IgG Nabi immunosuppressant BiopharmaceuticalsInc., Boca Raton, FL Intron A and Zadaxin IFN-α2b/α1-thymosin RegeneRxBiopharmiceuticals Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc, SanMateo, CA Levovirin IMPDH inhibitor Ribapharm Inc., Costa Mesa, CAViramidine Ribavirin Prodrug Ribapharm Inc., Costa Mesa, CA Heptazymeribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO Intron A IFN-α2bSchering-Plough Corporation, Kenilworth, NJ PEG-Intron PEGylated IFN-α2bSchering-Plough Corporation, Kenilworth, NJ Rebetron IFN-α2b/ribavirinSchering-Plough Corporation, Kenilworth, NJ Ribavirin ribavirinSchering-Plough Corporation, Kenilworth, NJ PEG-Intron/RibavirinPEGylated IFN- Schering-Plough α2b/ribavirin Corporation, Kenilworth, NJZadazim Immune modulator SciClone Pharmaceuticals Inc., San Mateo, CARebif IFN-β1a Serono, Geneva, Switzerland IFN-β and EMZ701 IFN-β andEMZ701 Transition Therapeutics Inc., Ontario, Canada Batabulin (T67)β-tubulin inhibitor Tularik Inc., South San Francisco, CA MerimepodibIMPDH inhibitor Vertex Pharmaceuticals (VX-497) Inc., Cambridge, MATelaprevir NS3 serine protease Vertex Pharmaceuticals (VX-950,LY-570310) inhibitor Inc., Cambridge, MA/ Eli Lilly and Co. Inc.,Indianapolis, IN Omniferon natural IFN-α Viragen Inc., Plantation, FLXTL-6865 (XTL-002) monoclonal antibody XTL Biopharmaceuticals Ltd.,Rehovot, Isreal HCV-796 NS5B Replicase Wyeth/Viropharma Inhibitor NM-283NS5B Replicase Idenix/Novartis Inhibitor GL-59728 NS5B Replicase GeneLabs/Novartis Inhibitor GL-60667 NS5B Replicase Gene Labs/NovartisInhibitor 2′C MeA NS5B Replicase Gilead Inhibitor PSI 6130 NS5BReplicase Roche Inhibitor R1626 NS5B Replicase Roche Inhibitor SCH503034 serine protease Schering Plough inhibitor NIM811 CyclophilinInhibitor Novartis Suvus Methylene blue Bioenvision Multiferon Longlasting IFN Viragen/Valentis Actilon (CPG10101) TLR9 agonist ColeyInterferon-β Interferon-β-1a Serono Zadaxin Immunomodulator SciclonePyrazolopyrimidine HCV Inhibitors Arrow Therapeutics Ltd. compounds andsalts From WO 2005047288 2′C Methyl adenosine NS5B Replicase MerckInhibitor GS-9132 (ACH-806) HCV Inhibitor Achillion/Gilead

DESCRIPTION OF SPECIFIC EMBODIMENTS

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd “for saturated, “MW” for molecular weight,“mp” for melting point, “ee” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “¹H” for proton, “δ” for delta, “s” forsinglet, “d” for doublet, “t” for triplet, “q” for quartet, “m” formultiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”,and “Z” are stereochemical designations familiar to one skilled in theart.

2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylicacid

Excess NaOH (10 mL, 1N aq) was added to a stirring solution of methyl2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylate(3.0 g, 6.89 mmol) in EtOH (34 mL) and THF (34 mL). It was allowed tostir at 60° C. overnight. The mixture was then heated to 67° C. andallowed to stir for 4 more hours. The mixture was concentrated thendiluted with EtOAc and washed with 1M HCl, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated to give thetitled compound (2.7 g, 96%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31-1.38(m, 6H) 2.99 (s, 3H) 4.63-4.73 (m, 1H) 7.32-7.41 (m, 2H) 8.00-8.08 (m,2H) 8.88 (s, 2H) 13.05 (s, 1H). LC-MS retention time: 1.03 min; m/z(MH−): 406. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide

Ammonia (6.1 ml, 12.2 mmol, 2M in MeOH) was added to a stirring solutionof HATU (1.1 g, 2.95 mmol) and2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxylicacid (1.0 g, 2.46 mmol) in DMF (20 ml) at 0° C. It was allowed to warmto rt and stir for 1 hr. The mixture was diluted with EtOAc and washedwith sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4,filtered and concentrated to give the title compound (925 mg, 93%). 1HNMR (300 MHz, DMSO-D6) δ ppm 1.30-1.37 (m, 6H) 2.98 (s, 3H) 4.64-4.77(m, 1H) 7.19 (s, 1H) 7.30-7.41 (m, 2H) 7.54 (s, 1H) 7.63-7.71 (m, 1 H)7.89 (s, 1H) 7.93-8.02 (m, 2H) 8.85 (s, 1H). LC-MS retention time: 1.26min; m/z (MH+) 407. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

N-(3-cyano-2-(4-fluorophenyl)-5-isopropoxybenzofuran-6-yl)methanesulfonamide

Trifluoroacetic anhydride (375 μL, 2.66 mmol) was added to a stirringsolution of DIEA (928 μL, 5.31 mmol), 2-(4-fluorophenyl)-5-isopropoxy-6(methylsulfonamido) benzofuran-3-carboxamide (300 mg, 0.738 mmol) inCH2Cl2 (4 mL) and THF (4 mL) at 0° C. for 1 hour. The mixture wasdiluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated. The cruderesidue was purified by on silica gel (Biotage, gradient EtOAc/hexanes,fraction collection at λ=254 nm) to give the title compound (143 mg,50%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.28-1.41 (m, 6H) 3.01 (s, 3H)4.77-4.95 (m, 1H) 7.35 (s, 1H) 7.44-7.57 (m, 2 H) 7.68 (s, 1H) 8.04-8.20(m, 2H) 9.01 (s, 1H). LC-MS retention time: 1.65 min; m/z (MH−): 387. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid

Cesium carbonate (3.5 g, 10.7 mmol) was added to Pd(Ph3P)₄ (108 mg,0.093 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (3.0 g, 7.19 mmol), 3-boronobenzoic acid (1.97g, 11.86 mmol). Dioxane (60 ml) and water (12 ml) was added at rt. Thereaction was degassed 3× and then heated to 95° C. and allowed to stirovernight. It was allowed to cool to rt. The mixture was diluted withEtOAc and washed with 1M HCl, and sat NaCl. The precipitate that formedwas filtered and dried overnight at 55° C. under vacuum. The remainingorganic phase was concentrated and triturated with DCM, followed by hotDCE and finally hot MeOH to afford the titled compound which wascombined with the previously collected precipitate (2.4 g, 87%). LC-MSretention time: 1.19 min; m/z (MH+): 390. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode.

Ethyl 2-(4-fluorophenyl)-5-hydroxy-4-nitrobenzofuran-3-carboxylate andethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate

Nitric acid (21 μL, 0.33 mmol) was added to a stirring solution of ethyl2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (100 mg, 0.33 mmol)in chloroform (3.3 mL) at −20° C. It was allowed to stir for 10 min. A9:2 ratio of ethyl2-(4-fluorophenyl)-5-hydroxy-4-nitrobenzofuran-3-carboxylate to ethyl2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate wasobserved. The crude reaction was purified on silica gel (Biotage,EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give thetitled compounds:

Ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate

1H NMR (500 MHz, DMSO-d₆) δ ppm 10.92 (1H, s), 8.33 (1H, s), 8.03-8.11(2H, m), 7.69 (1H, s), 7.43 (2H, t, J=8.85 Hz), 4.34 (2H, q, J=7.22 Hz),1.33 (3H, t, J=7.17 Hz). LC-MS retention time: 1.79 min; m/z (MH−): 344.LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Ethyl 2-(4-fluorophenyl)-5-hydroxy-4-nitrobenzofuran-3-carboxylate

1H NMR (500 MHz, DMSO-d₆) δ ppm 11.03 (1H, s), 7.92-8.01 (2H, m), 7.86(1H, d, J=9.16 Hz), 7.42 (2H, t, J=8.85 Hz), 7.17 (1H, d, J=8.85 Hz),4.20 (2H, q, J=7.12 Hz), 1.21 (3H, t, J=7.17 Hz). LC-MS retention time:1.56 min; m/z (MH−): 344. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode.

Ethyl2-(4-fluorophenyl)-4-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate

Triethylamine (91 μL, 0.652 mmol) was added to a stirring solution of1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(116 mg, 0.326 mmol) and ethyl2-(4-fluorophenyl)-5-hydroxy-4-nitrobenzofuran-3-carboxylate (75 mg,0.217 mmol) in DCM (2.2 mL). The crude reaction was purified on silicagel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm)to give titled compound (78 mg, 75%). 1H NMR (500 MHz, DMSO-d₆) δ ppm11.03 (1H, s), 7.92-8.01 (2H, m), 7.86 (1H, d, J=9.16 Hz), 7.42 (2H, t,J=8.85 Hz), 7.17 (1H, d, J=8.85 Hz), 4.20 (2H, q, J=7.12 Hz), 1.21 (3H,t, J=7.17 Hz). LC-MS retention time: 1.91 min; m/z (MH+): no iondetected. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

Ethyl2-(4-fluorophenyl)-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate

Step 1: Cesium carbonate (333 mg, 1.021 mmol) was added to Pd(Ph3P)₄ (39mg, 0.034 mmol), ethyl2-(4-fluorophenyl)-4-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate(325 mg, 0.681 mmol), 3-boronobenzoic acid (169 mg, 1.021 mmol). Dioxane(5.6 mL) and water (1.1 mL) was added at rt. The reaction was degassed3× and heated to 90° C. overnight. It was allowed to cool. The mixturewas diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated to give them-acid.

Step 2: The crude m-acid was diluted with DMF (5 mL) and treated withHATU (388 mg, 1.021 mmol), 2-phenylpropan-2-amine (138 mg, 1.021 mmol),and DIEA (357 μL, 2.043 mmol) and allowed to stir at rt for 1 hr. Themixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl.The organic phase was dried over Na2SO4, filtered and concentrated togive the titled compound which was purified on silica gel (Biotage 25+Mcolumn, EtOAc/hexanes gradient; Rf˜0.2 for 20% EtOAc/hexanes; fractioncollection at λ=254 nm) to give a light yellow solid (294 mg, 76%).LC-MS retention time: 1.97 min; m/z (MH+): 567. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Ethyl2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate

Triethylamine (121 μL, 0.869 mmol) was added to a stirring solution of1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(155 mg, 0.434 mmol) and ethyl2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (100 mg,0.290 mmol) in DCM (3 mL). It was allowed to stir overnight. The mixtureconcentrated and was purified on silica gel (Biotage, EtOAc/hexanesgradient, fraction collection at λ=254 nm) to give the titled compound(140 mg, 100%). 1H NMR (300 MHz, DMSO-d₆) δ ppm 8.91 (1H, s), 8.10-8.19(3H, m), 7.48 (2H, t, J=8.97 Hz), 4.37 (2H, q, J=7.07 Hz), 1.34 (3H, t,J=6.95 Hz). LC-MS retention time: 1.91 min; m/z (MH+): no ion detected.LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid

Excess NaOH (11 ml, 11.00 mmol, 1M aq) was added to a stirring solutionof ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate(1.9 g, 5.50 mmol) in EtOH (55 ml) and THF (55 ml) and was allowed tostir at 64° C. overnight. The mixture was concentrated and diluted withEtOAc and washed with 1M HCl, and sat NaCl. The organic phase was driedover Na2SO4, filtered and concentrated to give the titled compound (1.7g, quant.). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.31-7.48 (m, 2H) 7.71 (s,1H) 8.00-8.14 (m, 2H) 8.29 (s, 1H) 10.80 (s, 1H) 13.35 (s, 1H). LC-MSretention time: 0.99 min; m/z (MH−): 416. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yltrifluoromethanesulfonate

Step 1: Methanamine (4.4 ml, 8.83 mmol) was added to a stirring solutionof DIEA (3 ml, 17.65 mmol), BOP (2.9 g, 6.62 mmol), and2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylic acid (1.4 g,4.41 mmol) in DMF (44 ml) at 0° C. It was allowed to warm to rt and stirfor 1 hr. The mixture was concentrated and diluted with EtOAc and washedwith 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4,filtered and concentrated to give a crude product which was trituratedwith MeOH to give the methyl amide, nitro phenol-hmpa adduct (1.7 g,78%). Step 2: The hmpa-adduct (100 mg, 0.203 mmol) was taken up in EtOHand treated with 1M NaOH (609 μL, 0.609 mmol) at 70° C. It was allowedto stir overnight. The mixture was diluted with EtOAc and washed with 1MHCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated to give the nitro phenol (50 mg, 75%) as a brown solid.LC-MS retention time: 1.34 min; m/z (MH+): 331. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Step 3: Triethylamine (422 μL, 3.03 mmol) wasadded to a stirring solution of N-Phenylbis(trifluoromethane)sulfonimide(649 mg, 1.817 mmol) and2-(4-fluorophenyl)-5-hydroxy-N-methyl-6-nitrobenzofuran-3-carboxamide(400 mg, 1.211 mmol) in DCM (24 mL) at rt. The slurry was allowed tostir overnight. The mixture was diluted with EtOAc and washed with satNaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filteredand concentrated to give a crude residue which was purified on silicagel (Biotage, EtOAc/hexanes gradient, Rf˜0.2 in 30% EtOAc/hexanes,fraction collection at λ=254 nm) to give the titled compound (375 mg,67%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.83 (1H, s), 8.55-8.65 (1H, m),7.98-8.05 (2H, m), 7.95 (1H, s), 7.47 (2H, t, J=8.85 Hz), 2.84 (3H, d,J=4.58 Hz). LC-MS retention time: 1.96 min; m/z (MH−): 461. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate

Iron (211 mg, 3.79 mmol) was added to a stirring solution of2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yltrifluoromethanesulfonate (350 mg, 0.757 mmol) in EtOH (8.4 mL) and AcOH(8.4 mL) at rt and then was heated to 100° C. for 10 min. The mixturewas diluted with EtOAc and washed with 1M HCl, and sat NaCl followed by1M NaOH and brine. The organic phase was dried over Na2SO4, filtered andconcentrated to give a white solid which was 1:1 startingmaterial:product. It was resubjected to the reaction conditions for 15min and re-worked up to give the titled compound (275 mg, 84%). LC-MSretention time: 1.47 min; m/z (MH+): 433. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-(methylsulfonyl)methylsulfonamido)benzofuran-5-yltrifluoromethanesulfonate

Methanesulfonyl chloride (146 μL, 1.873 mmol) was added to a stirringsolution of6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (270 mg, 0.624 mmol) and DIEA (500 μL, 2.86mmol) in DCM (6.3 mL) at 25° C. It was allowed to stir for 1 hour andthen diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. Theorganic phase was dried over Na2SO4, filtered and concentrated. It waspurified on silica gel (Biotage, EtOAc/hexanes gradient, fractioncollection at λ=254 nm) to give the titled compound (300 mg, 82%). LC-MSretention time: 1.49 min; m/z (MH+): 589. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Azidotrimethylsilane (161 μL, 1.215 mmol) was added to a stirringsolution of5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(225 mg, 0.607 mmol) and dibutylstannanone (30 mg, 0.121 mmol) intoluene (6 mL) at rt. It was heated to 105° C. and allowed to stirovernight. The reaction, which remained a slurry, resulted in ˜70%conversion. Additional equiv of reagents and solvents were added and themixture was allowed to stir overnight at 105° C. The reaction wasallowed to cool and filtered to give the titled compound (205 mg, 82%).LC-MS retention time: 1.03 min; m/z (MH+): 414. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate

Trimethylsilyldiazomethane (500 μL, 1.00 mmol, 2M in diethyl ether) wasadded to a stirring solution of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(100 mg, 0.257 mmol) in diethyl ether (2.5 mL) at 25° C. It was allowedto stir for 2 hours. The mixture was concentrated to afford the titledcompound (100 mg, 97%). LC-MS retention time: 2.46 min; m/z (MH+): 404.LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where solvent A was10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10%H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode.

2-(4-fluorophenyl)-5-(3-formylphenyl)-N-methylbenzofuran-3-carboxamide

Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)₄ (20 mg,0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (150 mg, 0.359 mmol), 3-formylphenylboronicacid (59 mg, 0.395 mmol). Dioxane (3 mL) and water (600 μL) was added atrt. The reaction was heated to 90° C. overnight. The mixture was dilutedwith ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated and trituratedwith DCM to give the titled compound (55 mg, 41%). LC-MS retention time:1.49 min; m/z (MH+): 374. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode.

Ethyl5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate

Cesium carbonate (1.54 g, 4.71 mmol) was added to Pd(Ph3P)₄ (182 mg,0.157 mmol), ethyl2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate(1500 mg, 3.14 mmol), 3-(tert-butoxycarbonyl)phenylboronic acid (768 mg,3.46 mmol). Dioxane (26 mL) and water (5 mL) was added at rt. Thereaction was heated to 90° C. overnight. The reaction was allowed tocool was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl.The organic phase was dried over Na2SO4, filtered and concentrated andpurified on silica gel (Biotage, EtOAc/hexanes gradient, fractioncollection at λ=254 nm) to give to give the titled compound (1.10 g,69%). 1H NMR (300 MHz, DMSO-d₆) δ ppm 8.60 (1H, s), 8.08-8.18 (2H, m),8.02 (1H, s), 7.95-8.01 (1H, m), 7.88 (1H, s), 7.58-7.70 (2H, m), 7.46(2H, t, J=8.78 Hz), 4.34 (2H, q, J=7.20 Hz), 1.56 (9H, s), 1.27 (3H, t,J=7.14 Hz). LC-MS retention time: 2.13 min; m/z (MH+): parent does notionize. LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AVUV-Vis detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 5 ml/min, a gradient of 100% solventA/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where solvent A was5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5%H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determinedusing a Micromass Platform for LC in electrospray mode.

Ethyl6-amino-5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)benzofuran-3-carboxylate

Iron (28 mg, 0.495 mmol) was added to a stirring solution of ethyl5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate(50 mg, 0.099 mmol) in EtOH (495 μL) and AcOH (495 μL) at 100° C. It wasallowed to stir for 1 hr. The mixture was diluted with EtOAc and washedwith 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4,filtered and concentrated to give the titled compound (45 mg, 96%). 1HNMR (400 MHz, DMSO-d₆) d ppm 7.99-8.06 (2H, m), 7.89-7.96 (2H, m),7.65-7.72 (1H, m), 7.61 (1H, t, J=7.65 Hz), 7.55 (1H, s), 7.31-7.40 (2H,m), 7.00 (1H, s), 5.10 (2H, br. s.), 4.29 (2H, q, J=7.03 Hz), 1.56 (9H,s), 1.26 (3H, t, J=7.15 Hz). LC-MS retention time: 2.03 min; m/z (MH+):parent does not ionize. 420 (−tBu) was observed. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-V is detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Ethyl5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate

Step 1: Methanesulfonyl chloride (16 μL, 0.208 mmol) was added to astirring solution of ethyl6-amino-5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)benzofuran-3-carboxylate(90 mg, 0.189 mmol) in pyridine (2 mL) at rt. It was allowed to stir for6 hrs, then 8 uL of MsCl was added and the reaction was allowed to stirovernight. The reaction was concentrated and diluted with ethyl acetateand washed with sat NaHCO3, and sat NaCl. The organic phase was driedover Na2SO4, filtered and concentrated to give the NH sulfonamideintermediate. LC-MS retention time: 1.93 min; m/z (MH−): 552. LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Step 2: The crude residue was diluted with DMF (2 mL) and treated withDIEA (99 μL, 0.568 mmol) and Iodomethane (18 μL, 0.284 mmol) followed byNa2CO3 (20 mg). The reaction was allowed to stir for 3 days. The mixturewas diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. Theorganic phase was dried over Na2SO4, filtered and concentrated to givethe titled compound (100 mg, 93%). LC-MS retention time: 1.96 min; m/z(MH+): the parent does not ionize. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters XBridge 5u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

3-(3-(ethoxycarbonyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)benzoicacid

TFA (2 mL, 26.0 mmol) was added to a stirring solution of ethyl5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate(100 mg, 0.176 mmol) in DCE (9 mL) at 25° C. It was allowed to stir forseveral hours then concentrated to give the titled compound (92 mg,quant). 1H NMR (400 MHz, DMSO-d₆) δ ppm 8.05-8.12 (3H, m), 7.92-8.03(3H, m), 7.65-7.75 (1H, m), 7.53-7.64 (1H, m), 7.44 (2H, t, J=8.91 Hz),4.33 (2H, q, J=7.03 Hz), 3.12 (3H, s), 2.93 (3H, s), 1.26 (3H, t, J=7.15Hz). LC-MS retention time: 1.17 min; m/z (MH−): 510. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Ethyl2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate

DIEA (51 μL, 0.293 mmol) was added to a stirring solution of3-(3-(ethoxycarbonyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)benzoicacid (50 mg, 0.098 mmol), 2-phenylpropan-2-amine (26 mg, 0.195 mmol),HATU (56 mg, 0.147 mmol) in DMF (1 mL) at 25° C. It was allowed to stirfor 1 hour. The mixture was diluted with EtOAc and washed with 1M HCl,and sat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated to give the titled compound (50 mg, 81%). LC-MS retentiontime: 1.82 min; m/z (MH+): 629. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters XBridge 5u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylicacid

NaOH (500 μL, 0.500 mmol, 1M aq.) was added to a stirring solution ofethyl2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate(50 mg, 0.080 mmol) in Ethanol (795 μL) at 60° C. The slurry was allowedto stir overnight. DMF (2 mL) was added along with additional portion ofNaOH and the mixture was warmed to 70° C. and allowed to stir overnight.The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl.The organic phase was dried over Na2SO4, filtered and concentrated togive the titled compound (49 mg, quant). LC-MS retention time: 2.36 min;m/z (MH+): 601. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min wheresolvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid andsolvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MSdata was determined using a Micromass Platform for LC in electrospraymode.

Ethyl3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)benzoate

Cesium carbonate (1.69 g, 5.19 mmol) was added to Pd(Ph3P)₄ (250 mg,0.216 mmol),2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yltrifluoromethanesulfonate (2.00 g, 4.33 mmol),3-(ethoxycarbonyl)phenylboronic acid (1.01 g, 5.19 mmol). Dioxane (36mL) and water (7 mL) was added at rt and the mixture was degassed 3×.The reaction was heated to 90° C. overnight. It was allowed to cool. Themixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. Theorganic phase was dried over Na2SO4, Tilt and concentrated. The crudesolid was triturated with DCM to give the titled compound (1.70 g, 85%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55-8.61 (1H, m), 8.54 (1H, s),8.00-8.09 (3H, m), 7.95 (1H, s), 7.73 (1H, s), 7.61-7.70 (2H, m), 7.45(2H, t, J=8.91 Hz), 4.35 (2H, q, J=7.19 Hz), 2.83 (3H, d, J=4.52 Hz),1.34 (3H, t, J=7.03 Hz). LC-MS retention time: 1.62 min; m/z (MH+): 463.LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Ethyl3-(6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate

Iron (1.03 g, 18.4 mmol) was added to a stirring solution of ethyl3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)benzoate(1.70 g, 3.68 mmol) in EtOH (37 mL) and AcOH (37 mL) at 90° C. Theslurry was allowed to stir for 1 hour. The mixture was diluted withEtOAc and washed with 1M HCl, and sat NaCl followed by 1M NaOH and sat.NaCl. The organic phase was dried over Na2SO4, filtered and concentratedto give the titled compound (1.40 g 88%). ¹H NMR (400 MHz, DMSO-d₆) δppm 8.25-8.34 (1H, m), 8.00-8.03 (1H, m), 7.87-7.99 (3H, m), 7.69-7.75(1H, m), 7.63 (1H, t, J=7.65 Hz), 7.26-7.37 (2H, m), 7.20 (1H, s), 6.98(1H, s), 5.07 (2H, s), 4.35 (2H, q, J=7.03 Hz), 2.78 (3H, d, J=4.52 Hz),1.34 (3H, t, J=7.03 Hz). LC-MS retention time: 1.46 min; m/z (MH+): 433.LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

Ethyl3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(methylsulfonamido)benzofuran-5-yl)benzoate

Methanesulfonyl chloride (303 μL, 3.88 mmol) was added to a stirringsolution of ethyl3-(6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate(1.40 g, 3.24 mmol) in pyridine (32 mL) at 25° C. It was allowed to stirovernight at rt. The reaction was concentrated and was purified onsilica gel (Biotage, EtOAc/hexanes gradient, fraction collection atλ=254 nm) to give the titled compound (1.01 g, 61%). LC-MS retentiontime: 1.53 min; m/z (MH+): 511. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters XBridge 5u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

Step 1: (2-bromoethoxy)(tert-butyl)dimethylsilane (189 μL, 0.881 mmol)was added to a stirring suspension of Na2CO3 (311 mg, 2.94 mmol) andethyl3-(6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoatein DMF (6 mL) at 100° C. It was allowed to stir for 5 hrs, and thenallowed to cool to rt and stir overnight. The mixture was diluted withEtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase wasdried over Na2SO4, filtered and concentrated. LC-MS retention time: 2.12min; m/z (MH+): 669. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode. Step2: The residue was diluted with EtOH (10 mL) and treated with NaOH (2938μL, 2.94 mmol) and allowed to stir at 60° C. for 4 hours. The mixturewas diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated. Step 3: Thecrude residue was taken up in THF and treated with 1M HCl (making it 30%in THF). The reaction was allowed to stir for 1 hour. The mixture wasdiluted with EtOAc and washed with 1M HCl, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated to give thetitled compound (300 mg, 97%). LC-MS retention time: 1.09 min; m/z(MH+): 527. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

N-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)methanesulfonamideandN-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)-N-methylmethanesulfonamide

N,N-Dimethylformamide dimethyl acetal (500 μL, 3.76 mmol) and2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide(100 mg, 0.246 mmol) were combined and heated to 85° C. DMF (1 mL) wasadded. It was allowed to stir for 1 hr. The mixture was concentrated anddiluted with dioxane (200 μl), acetic acid (1 ml) and treated withhydrazine (154 μL, 4.92 mmol) and heated at 85° C. for several hours.The mixture was diluted with EtOAc and washed with sat NaHCO3, and satNaCl. The organic phase was dried over Na2SO4, filtered andconcentrated. The crude residue was purified by preparative reversephase HPLC on a C18 column using a suitably buffered gradient, andconcentrated to give to giveN-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)methanesulfonamide(25 mg, 0.058 mmol) andN-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)-N-methylmethanesulfonamide(11 mg, 0.025 mmol).N-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)methanesulfonamide.1H NMR (300 MHz, DMSO-D6) δ ppm 1.30-1.42 (m, 6H) 2.99 (s, 3H) 4.57-4.73(m, 1H) 7.24-7.40 (m, 2H) 7.57 (s, 1 H) 7.67 (s, 1H) 8.06-8.22 (m, 2H)8.68 (s, 1H). LC-MS retention time: 1.30 min; m/z (MH+): 431. LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC wereperformed using a Shimadzu-VP instrument with UV detection at 220 nm and254 nm. Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA,Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=10.71 min, purity=94%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=9.74 min,purity=97%.N-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)-N-methylmethanesulfonamide.1H NMR (300 MHz, DMSO-D6) δ ppm 1.29-1.41 (m, 6H) 3.04 (s, 3H) 3.19-3.24(m, 3H) 4.61-4.80 (m, 1H) 7.28-7.39 (m, 2H) 7.61 (s, 1H) 7.76 (s, 1H)8.08-8.27 (m, 2 H) 8.78 (s, 1H) 14.34 (s, 1H). LC-MS retention time:1.36 min; m/z (MH+) 345. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode. Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA,Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=11.30 min, purity=>95%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=10.21min, purity=>95%.

N-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)methanesulfonamide

Azidotrimethylsilane (34.2 μL, 0.257 mmol) was added to a stirringsolution of dibutyltin oxide (6.41 mg, 0.026 mmol) andN-(3-cyano-2-(4-fluorophenyl)-5-isopropoxybenzofuran-6-yl)methanesulfonamide(50 mg, 0.129 mmol) in dioxane (1.3 mL) at rt. It was subjected tomicrowave irradiation for 15 min at 150° C. It was treated withadditional equivalents of reagents and re-subjected for 30 min followedby 60 min. The mixture was concentrated and purified by preparativereverse phase HPLC on a C18 column using a suitably buffered gradient,and concentrated to give the titled compound (12 mg, 22%). 1H NMR (300MHz, DMSO-D6) δ ppm 1.29-1.39 (m, 6H) 3.01 (s, 3H) 4.62-4.81 (m, 1H)7.28-7.45 (m, 3H) 7.65 (s, 1H) 7.84-7.98 (m, 2H) 8.92 (s, 1H). LC-MSretention time: 1.04 min; m/z (MH+): 432. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=11.56 min,purity=94%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm,R_(t)=10.55 min, purity=96%.

General Procedure: m-Amide Coupling

DIEA (36 μL, 0.205 mmol) was added to a stirring solution of HATU (59mg, 0.154 mmol), the appropriate amine (0.164 mmol), and3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(40 mg, 0.103 mmol) in DMF (1 mL) at room temperature. It was allowed tostir overnight. The reaction was concentrated and purified bypreparative reverse phase HPLC on a C18 column using a suitably bufferedH₂O/CH₃CN gradient, and concentrated to give the expected product. Thisgeneral procedure was applied to Examples KP4 through KP14.

5-(3-(tert-butylmethyl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 1.54-1.57 (m, 9H) 2.94-2.99 (m, 6H) 7.25(t, 2H) 7.35-7.40 (m, 1H) 7.53 (t, 1H) 7.64-7.67 (m, 2H) 7.67-7.68 (m,1H) 7.72-7.77 (m, 1H) 7.88-7.90 (m, 1H) 7.92-7.97 (m, 2H). LC-MSretention time: 1.71 min; m/z (MH+): 459. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

2-(4-fluorophenyl)-5-(3-(1-(4-fluorophenyl)ethylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 8.10-8.15 (1H, m), 7.90-7.99 (3H, m), 7.84(2H, t, J=9.61 Hz), 7.63-7.72 (2H, m), 7.56 (1H, t, J=7.78 Hz),7.40-7.47 (2H, m), 7.22-7.29 (2H, m), 7.03-7.10 (2H, m), 5.24-5.30 (1H,m), 2.97 (3H, s), 1.59 (3H, d, J=7.02 Hz). LC-MS retention time: 1.67min; m/z (MH−): 509. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% MeOH/95% H₂O/10 mM ammoniumbicarbonate, Solvent B=95% MeOH/5% H₂O/10 mM ammonium bicarbonate, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 μm,R_(t)=15.64 min, purity=97%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=15.63 min, purity=98%.

(S)-2-(4-fluorophenyl)-5-(3-(1-(4-fluorophenyl)ethylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 8.13 (1 H, s), 7.91-7.99 (3H, m), 7.84(2H, t, J=9.31 Hz), 7.64-7.72 (2H, m), 7.56 (1H, t, J=7.78 Hz),7.41-7.48 (2H, m), 7.26 (2H, t, J=8.85 Hz), 7.02-7.10 (2H, m), 5.28 (1H,q, J=7.22 Hz), 2.97 (3H, s), 1.59 (3H, d, J=7.02 Hz). LC-MS retentiontime: 1.67 min; m/z (MH−): 509. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters XBridge 5u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95%H₂O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H₂O/10 mM ammoniumbicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C1 C-18,4.6×150 mm, 3 μm, R_(t)=15.55 min, purity=99%; Column: Waters XbridgePhenyl column 4 6×150 mm, 3.5 μm, R_(t)=15.34 min, purity=98%.

(R)-2-(4-fluorophenyl)-5-(3-(1-(4-fluorophenyl)ethylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 8.14 (1 H, s), 7.92-7.99 (3H, m),7.81-7.87 (2H, m), 7.65-7.72 (2H, m), 7.57 (1H, t, J=7.63 Hz), 7.42-7.47(2H, m), 7.23-7.29 (2H, m), 7.04-7.10 (2H, m), 5.28 (1 H, q, J=7.02 Hz),2.97 (3H, s), 1.59 (3H, d, J=7.02 Hz). LC-MS retention time: 1.66 min;m/z (MH−): 509. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% MeOH/95% H₂O/10 mM ammoniumbicarbonate, Solvent B=95% MeOH/5% H₂O/10 mM ammonium bicarbonate, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 μm,R_(t)=15.56 min, purity=99%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=15.33 min, purity=97%.

2-(4-fluorophenyl)-5-(3-(2-(4-fluorophenyl)propan-2-ylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 8.04-8.10 (1H, m), 7.89-7.99 (3H, m),7.76-7.86 (2H, m), 7.63-7.73 (2H, m), 7.56 (1 H, t, J=7.78 Hz),7.42-7.51 (2H, m), 7.26 (2H, t, J=8.70 Hz), 6.98-7.06 (2H, m), 2.98 (3H,s), 1.78 (6H, s). LC-MS retention time: 1.72 min; m/z (MH−): 523. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% MeOH/95% H₂O/10 mM ammonium bicarbonate, Solvent B=95%MeOH/5% H₂O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 μm, R_(t)=15.73 min,purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm,R_(t)=15.53 min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 8.09 (1H, s), 7.90-7.99 (3H, m), 7.74-7.89(1H, m), 7.63-7.72 (2H, m), 7.55 (1H, t, J=7.63 Hz), 7.47 (2H, d, J=7.32Hz), 7.31 (2H, t, J=7.78 Hz), 7.22-7.28 (2H, m), 7.19 (1H, t, J=7.32Hz), 2.97 (3H, s), 1.79 (6H, s). LC-MS retention time: 1.71 min; m/z(MH−): 505. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% MeOH/95% H₂O/10 mM ammoniumbicarbonate, Solvent B=95% MeOH/5% H₂O/10 mM ammonium bicarbonate, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 μm,R_(t)=15.79 min, purity=99%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=15.53 min, purity=98%.

2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

1H NMR (500 MHz, DMSO-d₆) δ ppm 9.35 (1H, s), 8.48-8.56 (1H, m), 8.24(1H, s), 7.96-8.04 (2H, m), 7.87-7.96 (3H, m), 7.75-7.82 (2H, m), 7.59(1H, t, J=7.63 Hz), 7.40 (2 H, t, J=8.70 Hz), 7.21-7.29 (4H, m), 7.16(1H, t, J=7.17 Hz), 2.86 (3H, d, J=4.58 Hz), 1.25-1.35 (4H, m). LC-MSretention time: 1.63 min; m/z (MH−): 503. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95%H₂O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H₂O/10 mM ammoniumbicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C1 C-18,4.6×150 mm, 3 μm, R_(t)=15.91 min, purity=96%; Column: Waters XbridgePhenyl column 4 6×150 mm, 3.5 μm, R_(t)=15.79 min, purity=95%.

2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclobutylcarbamoyl)phenyl)benzofuran-3-carboxamide

1H NMR (500 MHz, DMSO-d₆) δ ppm 9.18 (1H, s), 8.53 (1H, q, J=4.48 Hz),8.20 (1H, s), 8.01 (2 H, dd, J=8.85, 5.49 Hz), 7.92 (1H, d, J=1.22 Hz),7.87 (2H, dd, J=7.63, 1.53 Hz), 7.73-7.83 (2H, m), 7.57 (1H, t, J=7.78Hz), 7.52 (2H, d, J=7.32 Hz), 7.40 (2H, t, J=9.00 Hz), 7.33 (2H, t,J=7.78 Hz), 7.20 (1H, t, J=7.32 Hz), 2.87 (3H, d), 2.61-2.71 (2H, m),2.54-2.58 (2H, m), 2.01-2.11 (1H, m), 1.82-1.92 (1H, m). LC-MS retentiontime 2.42 min; m/z (MH+): 519. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C183.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=14.66min, purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5μm, Rt=13.13 min, purity=97%.

N-(2-(4-fluorophenyl)-5-isopropoxy-3-(1H-1,2,4-triazol-5-yl)benzofuran-6-yl)methanesulfonamide

1H NMR (500 MHz, DMSO-d₆) δ ppm 11.03 (1H, s), 7.92-8.01 (2H, m), 7.86(1H, d, J=9.16 Hz), 7.42 (2H, t, J=8.85 Hz), 7.17 (1H, d, J=8.85 Hz),4.20 (2H, q, J=7.12 Hz), 1.21 (3H, t, J=7.17 Hz).). LC-MS retentiontime: 1.70 min; m/z (MH+): 547. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters XBridge 5u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=14.86 min,purity=99%. Additional HPLC method 2: Solvent A=5% MeOH/95% H₂O/10 mMammonium bicarbonate, Solvent B=95% MeOH/5% H₂O/10 mM ammoniumbicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C-18, 4.6×150mm, 3 μm, R_(t)=17.53 min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(pyridin-4-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

1H NMR (500 MHz, DMSO-d₆) δ ppm 11.15 (1H, s), 8.64 (2H, d, J=6.41 Hz),8.48-8.55 (1H, m), 8.30 (1H, s), 8.05-8.08 (2H, m), 7.97-8.03 (6H, m),7.76-7.85 (2H, m), 7.71 (1H, t, J=7.78 Hz), 7.41 (2H, t, J=8.70 Hz),2.83-2.92 (3H, m). LC-MS retention time: 1.45 min; m/z (MH+): 466. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% MeOH/95% H₂O/10 mM ammonium bicarbonate, Solvent B=95%MeOH/5% H₂O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, R_(t)=15.11 min, purity=97%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=14.81min, purity=96%.

2-(4-fluorophenyl)-5-(3-(isobutyl(methyl)carbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

1H NMR (500 MHz, CD₃OD) δ ppm 7.93-7.98 (2H, m), 7.88-7.91 (1H, m),7.74-7.81 (1H, m), 7.63-7.70 (3H, m), 7.51-7.60 (1H, m), 7.32-7.41 (1H,m), 7.25 (2H, t), 3.43 (1H, d), 3.21 (1H, d), 3.10 (2 H, s), 3.03 (2H,s), 2.96 (3H, s), 2.10-2.21 (1H, m), 1.92-2.07 (1H, m), 1.01 (3 H, d),0.78 (3H, d). LC-MS retention time: 1.65 min; m/z (MH+): 459. LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

2-(4-fluorophenyl)-N-methyl-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Step 1: ethyl2-(4-fluorophenyl)-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate(300 mg, 0.529 mmol) was diluted with EtOH (10 mL) and treated with NaOH(2.1 mL, 2.12 mmol, 1N aq.) and the mixture, which became a slurry, wasallowed to stir overnight at 60° C. The reaction was diluted with EtOAcand washed with 1M HCl, and sat NaCl. The organic phase was dried overNa2SO4, filtered and concentrated.

Step 2: EDC (128 mg, 0.668 mmol) was added to a stirring solution of thecrude2-(4-fluorophenyl)-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylicacid (300 mg, 0.557 mmol), methanamine (306 μL, 0.613 mmol),1-hydroxy-7-azabenzotriazole (83 mg, 0.613 mmol), DIEA (204 μL, 1.170mmol) in DCM (5.5 mL) at rt. It was allowed to stir for 3 days. Theslurry had gone into solution over that period of time. The mixture wasconcentrated and purified on silica gel (Biotage, EtOAc/hexanesgradient, fraction collection at λ=254 nm) to give the titled compound(220 mg, 95%). 1H NMR (500 MHz, CD₃OD) δ ppm 7.90-7.99 (3H, m),7.85-7.90 (1H, m), 7.82-7.84 (1H, m), 7.49-7.56 (3H, m), 7.45 (2 H, d,J=7.32 Hz), 7.27-7.34 (4H, m), 7.19 (1H, t, J=7.32 Hz), 2.87 (3H, s),1.76 (6 H, s). LC-MS retention time: 1.62 min; m/z (MH+): 552. LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5μm, R_(t)=13.60 min, purity=94%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=12.66 min, purity=96%.

4-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Iron (25 mg, 0.453 mmol) was added to a stirring solution of2-(4-fluorophenyl)-N-methyl-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide(50 mg, 0.091 mmol) in ethanol (1 mL) and AcOH (1 mL) at rt. It wasplaced in a reaction block set to 100° C. It was allowed to stir for 1hr. The mixture was allowed to cool and was diluted with EtOAc andwashed with 1M HCl, followed by 1N NaOH and sat NaCl. The organic phasewas dried over Na2SO4, filtered and concentrated and triturated withEt2O to give the titled compound (28 mg, 56%). 1H NMR (300 MHz, CD₃OD) δppm 7.83-7.89 (1H, m), 7.73-7.81 (3H, m), 7.52-7.64 (2H, m), 7.42-7.49(2H, m), 7.10-7.35 (6H, m), 6.98 (1H, d, J=8.42 Hz), 2.87 (3H, s), 1.76(6H, s). LC-MS retention time: 2.33 min; m/z (MH+): 522. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode. Additional HPLC method: SolventA=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm,R_(t)=14.17 min, purity=97%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=12.84 min, purity=98%.

4-acetamido-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

4-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide(20 mg, 0.038 mmol) was diluted in pyridine (1 mL) and treated withexcess acetyl chloride (10 μL). The reaction was allowed to stir for 2hours. The mixture was concentrated and diluted with MeOH (1 mL). Theproduct began to crash out, it was sonicated and filtered and washedwith MeOH to afford the titled compound (8 mg, 34%). 1H NMR (500 MHz,DMSO-d₆) δ ppm 9.41 (1H, s), 8.43 (1H, s), 8.31-8.38 (1H, m), 7.88-7.92(1H, m), 7.82-7.87 (2H, m), 7.80 (1H, d, J=7.63 Hz), 7.71 (1H, d, J=8.55Hz), 7.54-7.60 (1H, m), 7.43-7.49 (2H, m), 7.36-7.43 (5H, m), 7.28 (2H,t, J=7.78 Hz), 7.17 (1H, t, J=7.32 Hz), 2.76 (3H, d), 1.79 (3H, s), 1.69(6H, s). LC-MS retention time 1.42 min; m/z 564 (MH+). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5μm, R_(t)=12.00 min, purity=96%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=11.26 min, purity=95%.

2-(4-fluorophenyl)-N-methyl-6-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Step 1: cesium carbonate (143 mg, 0.440 mmol) was added to Pd(Ph3P)₄ (17mg, 0.015 mmol), ethyl2-(4-fluorophenyl)-6-nitro-5-(trifluoromethylsulfonyloxy)benzofuran-3-carboxylate(140 mg, 0.293 mmol), 3-boronobenzoic acid (73 mg, 0.440 mmol). Dioxane(2.5 mL) and water (500 μL) was added at rt. The reaction was degassed3× and heated to 90° C. overnight. It was allowed to cool. The mixturewas diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated. Step 2: Theresidue was diluted with DMF and treated with HATU (167 mg, 0.440 mmol),2-phenylpropan-2-amine (60 mg, 0.440 mmol), and DIEA (154 μL, 0.880mmol) and allowed to stir at rt overnight. The mixture was diluted withEtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase wasdried over Na2SO4, filtered and concentrated and purified on silica gel(Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) togive ethyl2-(4-fluorophenyl)-6-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylate.(LC-MS retention time: 1.97 min; m/z (MH+): 567. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode) Step 3: This material was treated with NaOH (1mL, 1.000 mmol) in ethanol (2.93 mL) at 60° C. for 2 hr then allowed tostir overnight while cooling to rt. The reaction was heated to 60° C.for 3 hrs. The mixture was diluted with EtOAc and washed with 1M HCl,and sat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated. Step 4: EDC (58 mg, 0.301 mmol), methanamine (1 mL, 2.000mmol), 1-hydroxy-7-azabenzotriazole (38 mg, 0.276 mmol), DIEA (92 μL,0.526 mmol) was added to the residue in DCE (2.5 mL) at rt. It wasallowed to stir for 3 days. The slurry had gone into solution over thatperiod of time. The crude reaction was purified on silica gel (Biotage,EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give thetitled compound (112 mg, 81%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.32 (1H,s), 7.97-8.06 (2H, m), 7.82-7.90 (2H, m), 7.75 (1H, s), 7.47-7.56 (2H,m), 7.45 (2H, d, J=7.32 Hz), 7.31 (4H, t, J=8.09 Hz), 7.18 (1H, t,J=7.32 Hz), 2.94 (3H, s), 1.77 (6H, s). LC-MS retention time: 3.10 min;m/z (MH+): 552. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min wheresolvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent Bwas 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode. Additional HPLCmethod: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5%H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150mm, 3.5 μm, R_(t)=14.12 min, purity=96%; Column: Waters Xbridge Phenylcolumn 4 6×150 mm, 3.5 μm, R_(t)=12.98 min, purity=97%.

6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Iron (68 mg, 1.22 mmol) was added to a stirring solution of2-(4-fluorophenyl)-N-methyl-6-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide(112 mg, 0.203 mmol) in ethanol (2.3 mL) and AcOH (2.3 mL) at rt. It wasplaced in a reaction block set to 100° C. and allowed to stir for 1 hr.The mixture was allowed to cool and was diluted with EtOAc and washedwith 1M HCl, followed by 1N NaOH and sat NaCl. The organic phase wasdried over Na2SO4, filtered and concentrated and triturated with Et2O togive the titled compound (52 mg, 47%). 1H NMR (500 MHz, CD₃OD) δ ppm6.58-6.65 (3H, m), 6.52 (1H, d, J=7.63 Hz), 6.37 (1H, d, J=7.93 Hz),6.30 (1H, t, J=7.63 Hz), 6.18 (2H, d, J=7.32 Hz), 6.08 (1H, s), 6.03(2H, t, J=7.78 Hz), 5.88-5.97 (3H, m), 5.73 (1H, s), 1.65 (3H, s), 0.50(6H, s). LC-MS retention time 1.54 min; m/z (MH−): 520. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5μm, R_(t)=15.11 min, purity=95%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, Rt=11.11 min, purity=94%.

2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Step 1: DIEA (134 μL, 0.765 mmol) was added to Pd(Ph3P)₄ (30 mg, 0.025mmol),2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-(methylsulfonyl)methylsulfonamido)benzofuran-5-yltrifluoromethanesulfonate (150 mg, 0.255 mmol),3-(ethoxycarbonyl)phenylboronic acid (74 mg, 0.382 mmol). Dioxane (5 mL)and water (1 mL) was added at rt. The reaction was degassed 3× andheated to 90° C. overnight. It was allowed to cool and left to stir for3 days at rt. Step 2: The mixture was concentrated and diluted with EtOH(5 mL) and treated with excess 1N NaOH (˜1 mL) and allowed to stir at rtovernight to give the meta-acid. The mixture was diluted with EtOAc andwashed with 1M HCl, and 1M HCl. The organic phase was dried over Na2SO4,filtered and concentrated. Step 3: The crude residue was diluted withDMF (5 mL) and treated with HATU (145 mg, 0.382 mmol),2-phenylpropan-2-amine (52 mg, 0.382 mmol) and DIEA (134 μL, 0.765 mmol)and allowed to stir at rt overnight. The mixture was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered gradient, and concentrated. The isolated titledcompound was re-purified on silica gel (Biotage, EtOAc/hexanes gradient,Rf˜0.2 50% EtOAc/hexanes, fraction collection at λ=254 nm) to give thetitled compound (7 mg, 4%). 1H NMR (500 MHz, CD₃OD) δ ppm 7.94-8.01 (2H,m), 7.92 (1H, s), 7.83 (1H, d, J=7.63 Hz), 7.77 (1H, s), 7.63-7.68 (2H,m), 7.59 (1H, t, J=7.63 Hz), 7.46 (2H, d, J=7.32 Hz), 7.24-7.32 (4H, m),7.18 (1H, t, J=7.32 Hz), 2.94 (3H, s), 2.88 (3H, s), 1.77 (6H, s). LC-MSretention time: 2.25 min; m/z (MH+): 600. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/0.1%TFA and solvent B was 5% H2O/95% acetonitrile/0.1% TFA. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, SolventB=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: WatersSunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=12.87 min, purity=96%; Column:Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, Rt=11.97 min,purity=98%.

2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Step 1: methanesulfonyl chloride (10 μL, 0.128 mmol) was added to astirring solution of6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide(50 mg, 0.096 mmol) in pyridine (1 mL) at rt. It was allowed to stir for2 hours and then concentrated and diluted with EtOAc and washed with satNaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filteredand concentrated. Step 2: The crude residue was dissolved in DMF (1 mL)and treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (102 μL,0.479 mmol) and Na2CO3 (31 mg, 0.288 mmol) at rt. It was heated to 100°C. for 4 hours and then diluted with EtOAc and washed with sat NaHCO3,and sat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated. Step 3: The crude residue was taken up in THF (2 mL) andtreated with 2 mL of 1N HCl. and allowed to stir at rt for 1 hr. Themixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl.The organic phase was dried over Na2SO4, filtered and concentrated andtriturated with Et2O to give the titled compound (25 mg, 39%). ¹H NMR(500 MHz, CD₃OD) δ ppm 8.14-8.21 (1H, m), 7.95-8.04 (2H, m), 7.83-7.87(1H, m), 7.76-7.81 (1H, m), 7.66-7.74 (2H, m), 7.56 (1H, t, J=7.63 Hz),7.41-7.49 (2H, m), 7.24-7.33 (4H, m), 7.17 (1H, t, J=7.32 Hz), 2.94 (3H,s), 1.76 (6H, s). LC-MS retention time 1.42 min; m/z (MH+): 644. LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5μm, R_(t)=12.26 min, purity=96%; Additional HPLC method: Solvent A=5%MeOH/95% H₂O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H₂O/10 mMammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C-18,4.6×150 mm, 3 μm, R_(t)=13.61 min, purity=94%.

5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Cesium carbonate (187 mg, 0.575 mmol) was added to Pd(Ph3P)₄ (22 mg,0.019 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (160 mg, 0.383 mmol), 3-cyanophenylboronicacid (85 mg, 0.575 mmol). Dioxane (3 mL) and water (600 μL) was added atrt. The reaction was degassed 3× and heated to 90° C. overnight. It wasallowed to cool. The mixture was diluted with EtOAc and washed with 1MHCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated. The crude residue was taken up in DCM. A white precipitateformed which was filtered to give the titled compound. The filtrate waspurified on silica gel (Biotage, EtOAc/hexanes gradient, Rf˜0.4:50%EtOAc/Hex, fraction collection at λ=254 nm) to give the titled compoundwhich was combined with the previously collected precipitate (85 mg,60%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.46-8.53 (1H, m), 8.24 (1H, s),8.09 (1H, d, J=7.93 Hz), 7.99-8.05 (2H, m), 7.96 (1H, d, J=1.53 Hz),7.85 (1H, d, J=7.63 Hz), 7.74-7.82 (2H, m), 7.70 (1H, t, J=7.78 Hz),7.40 (2H, t, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz). LC-MS retention time:2.17 min; m/z (MH+): 371. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid andsolvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, SolventB=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: WatersSunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=13.59 min, purity=99%; Column:Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=12.29 min,purity=99%.

2-(4-fluorophenyl)-5-(3-(5-isopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamide

Isobutyryl chloride (90 mg, 0.847 mmol) was added to a stirring solutionof5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(50 mg, 0.085 mmol) in pyridine (1 mL) at 100° C. It was allowed to stirovernight. The reaction was concentrated and diluted with EtOH (3 mL)and treated with excess 1N NaOH (500 μL) and stirred at 60° C. for 2hours to hydrolyze the acylated amide. The mixture was filtered and thefiltrate was diluted with EtOAc and washed with sat NaHCO3, and satNaCl. The organic phase was dried over Na2SO4, filtered and concentratedand purified on silica gel (Biotage, EtOAc/hexanes gradient, fractioncollection at λ=254 nm) to give the titled compound (8 mg, 20%). 1H NMR(500 MHz, CD₃OD) δ ppm 8.31-8.35 (1H, m), 8.03 (1H, d, J=7.94 Hz),7.95-8.00 (3H, m), 7.93 (1H, d, J=7.93 Hz), 7.67-7.74 (3H, m), 7.25-7.30(2H, m), 3.37-3.40 (1H, m), 2.99 (3H, s), 1.49 (6H, d, J=7.02 Hz). LC-MSretention time: 2.28 min; m/z (MH+): 456. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=14.30min, purity=94%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5μm, R_(t)=12.50 min, purity=93%.

2-(4-fluorophenyl)-5-(1H-indol-4-yl)-N-methylbenzofuran-3-carboxamide

Cesium carbonate (176 mg, 0.539 mmol) was added to Pd(Ph3P)₄ (20.77 mg,0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (150 mg, 0.359 mmol), 1H-indol-4-ylboronicacid (87 mg, 0.539 mmol). Dioxane (3 mL) and water (600 μL) was added atrt. The reaction was degassed 3× and then heated to 90° C. overnight. Itwas allowed to cool. The mixture was diluted with ethyl acetate andwashed with sat NaHCO3, and sat NaCl. The organic phase was dried overNa2SO4, filtered and concentrated and purified on silica gel (Biotage,EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give thetitled compound (66 mg, 46%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 11.28 (1H,br. s.), 8.48-8.57 (1H, m), 7.98-8.07 (2H, m), 7.86 (1H, br. s.), 7.79(1H, d, J=8.24 Hz), 7.69 (1H, d, J=7.93 Hz), 7.37-7.47 (4H, m), 7.21(1H, t, J=7.63 Hz), 7.14 (1H, d, J=7.02 Hz), 6.60 (1H, br. s.), 2.84(3H, d, J=4.27 Hz). LC-MS retention time: 1.53 min; m/z (MH+): 385. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5μm, R_(t)=13.46 min, purity=99%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, Rt=12.27 min, purity=97%.

5-(3-(2-benzyl-2H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Benzyl bromide (29 μL, 0.242 mmol) was added to a stirring solution of5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(50 mg, 0.121 mmol) and Na2CO3 (26 mg, 0.242 mmol) in DMF (1.2 mL) at100° C. It was allowed to stir overnight. The mixture was concentratedand purified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (12 mg, 19%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.48-8.56(1H, m), 8.30-8.35 (1H, m), 8.06 (1H, d, J=7.63 Hz), 7.98-8.03 (2H, m),7.90-7.93 (2 H, m), 7.78-7.83 (1H, m), 7.72-7.77 (1H, m), 7.69 (1H, t,J=7.78 Hz), 7.36-7.46 (7H, m), 6.04 (2H, s), 2.86 (3H, d, J=4.58 Hz).LC-MS retention time: 1.78 min; m/z (MH+): 504. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=15.69 min,purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm,R_(t)=13.95 min, purity=98%.

(R)-2-(4-fluorophenyl)-5-(3-(4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamide

Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(40 mg, 0.108 mmol) and (R)-2-amino-3-methylbutan-1-ol (111 mg, 1.08mmol) in PhCl (3 mL) at rt. It was subjected for two iterations tomicrowave irradiation for 1 hr at 200° C. The mixture was concentratedand purified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (13 mg, 25%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.24 (1H,s), 7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz),7.63-7.69 (2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.55 Hz),4.52 (1H, t, J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.14-4.22 (1H, m),2.98 (3H, s), 1.87-1.97 (1H, m), 1.04 (3H, d, J=7.02 Hz), 0.97 (3H, d,J=6.71 Hz). LC-MS retention time 1.64 min; m/z (MH+): 457. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode. Additional HPLC method: SolventA=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm,R_(t)=10.13 min, purity=95%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 μm, R_(t)=10.58 min, purity=94%.

(S)-2-(4-fluorophenyl)-5-(3-(4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)-N-methylbenzofuran-3-carboxamide

Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(40 mg, 0.108 mmol) and (S)-2-amino-3-methylbutan-1-ol (111 mg, 1.080mmol) in PhCl (3 mL) at rt. It was subjected for two 1 hr iterations tomicrowave irradiation at 200° C. The reaction was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (9 mg, 17%). ¹H NMR (500 MHz, CD₃OD) δ ppm 8.24 (1H, s),7.93-7.99 (2H, m), 7.89-7.93 (2H, m), 7.86 (1H, d, J=7.63 Hz), 7.63-7.69(2H, m), 7.56 (1H, t, J=7.78 Hz), 7.26 (2H, t, J=8.70 Hz), 4.52 (1H, t,J=9.31 Hz), 4.30 (1H, t, J=8.09 Hz), 4.15-4.22 (1H, m), 2.98 (3H, s),1.86-1.96 (1H, m), 1.04 (3H, d, J=6.71 Hz), 0.97 (3H, d, J=6.71 Hz).LC-MS retention time: 1.63 min; m/z (MH+): 457. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=10.06min, purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5μm, R_(t)=10.53 min, purity=95%.

2-(4-fluorophenyl)-5-(3-(2-isobutyl-2H-tetrazol-5-yl)phenyl)-N-methylbenzofuran-3-carboxamide

1-bromo-2-methylpropane (23 mg, 0.169 mmol) was added to a stirringsolution of5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100°C. It was allowed to stir overnight. The mixture was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (15 mg, 38%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.49-8.56(1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.63 Hz), 7.99-8.04 (2H, m),7.87-7.94 (2H, m), 7.79-7.84 (1H, m), 7.73-7.78 (1H, m), 7.70 (1 H, t,J=7.63 Hz), 7.41 (2H, t, J=8.70 Hz), 4.62 (2H, d, J=7.32 Hz), 2.87 (3H,d, J=4.27 Hz), 2.31-2.39 (1H, m), 0.95 (6H, d, J=6.71 Hz). LC-MSretention time: 2.09 min; m/z (MH+): 470. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=16.08min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5μm, R_(t)=13.89 min, purity=99%.

5-(3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Zinc chloride (1 mg) was added to a stirring solution of5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(40 mg, 0.108 mmol) and 2-amino-2-methylpropan-1-ol (10 mg, 0.108 mmol)in PhCl (3 mL) at 130° C. It was allowed to stir for 7 days. ˜20%conversion was observed. Additional amounts of ZnCl (8 mg) and2-amino-2-methylpropan-1-ol (50 mg) were added and the reaction washeated in the microwave for 1 hr at 200° C. The reaction had progressed˜50%. The mixture was concentrated and purified on silica gel (Biotage,EtOAc/hexanes gradient, Rf˜0.2 in 50% EtOAc/hexanes; fraction collectionat λ=254 nm) followed by preparative reverse phase HPLC on a C18 columnusing a suitably buffered H₂O/CH₃CN gradient, and concentrated to givethe titled compound (7 mg, 14%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.24 (1H,s), 7.97 (2H, dd, J=8.09, 5.65 Hz), 7.93 (1H, s), 7.88 (2H, dd, J=11.44,8.39 Hz), 7.68 (2H, s), 7.57 (1H, t, J=7.78 Hz), 7.27 (2H, t, J=8.55Hz), 4.25 (2H, s), 2.99 (3H, s), 1.42 (6H, s). LC-MS retention time 1.60min; m/z (MH+): 443. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, SolventB=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: WatersSunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=12.24 min, purity=95%; Column:Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=10.02 min,purity=95%.

2-(4-fluorophenyl)-5-(3-(2-isopropyl-2H-tetrazol-5-yl)phenyl)-N-methylbenzofuran-3-carboxamide

2-iodopropane (29 mg, 0.169 mmol) was added to a stirring solution of5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100°C. It was allowed to stir overnight. The mixture was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (12 mg, 30%). 1H NMR (500 MHz, DMSO-d₆) δ ppm 8.49-8.57(1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.32 Hz), 7.99-8.05 (2H, m),7.87-7.94 (2H, m), 7.79-7.83 (1H, m), 7.72-7.78 (1H, m), 7.70 (1H, t,J=7.78 Hz), 7.41 (2H, t, J=8.70 Hz), 5.17-5.27 (1H, m), 2.87 (3H, d,J=4.58 Hz), 1.66 (6H, d, J=6.71 Hz). LC-MS retention time: 2.02 min; m/z(MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent Bwas 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode. Additional HPLCmethod: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5%H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150mm, 3.5 μm, R_(t)=15.35 min, purity=96%; Column: Waters Xbridge Phenylcolumn 4 6×150 mm, 3.5 μm, R_(t)=13.39 min, purity=97%.

(R)-2-(4-fluorophenyl)-N-methyl-5-(3-(4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)benzofuran-3-carboxamide

Zinc chloride (8 mg, 0.054 mmol) was added to a stirring solution of5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(40 mg, 0.108 mmol) and (R)-2-amino-2-phenylethanol (148 mg, 1.080 mmol)in PhCl (3 mL) at rt. It was subjected to two iterations of microwaveirradiation at 200° C. for 1 hr. The material was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (7 mg, 13%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.33 (1H, s),7.94-8.00 (4H, m), 7.91 (1H, d, J=7.94 Hz), 7.64-7.73 (2H, m), 7.61 (1H,t, J=7.78 Hz), 7.32-7.42 (6H, m), 7.26 (2H, t, J=8.55 Hz), 5.45 (1H, t,J=9.16 Hz), 4.94 (1 H, t, J=9.31 Hz), 4.36 (1H, t, J=8.24 Hz), 2.97 (3H,s). LC-MS retention time 1.75 min; m/z (MH+): 491. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a WatersXBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% MeOH/95% H₂O/10 mM ammonium bicarbonate, Solvent B=95%MeOH/5% H₂O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, R_(t)=18.32 min, purity=97%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=18.11min, purity=97%.

(S)-2-(4-fluorophenyl)-N-methyl-5-(3-(4-phenyl-4,5-dihydrooxazol-2-yl)phenyl)benzofuran-3-carboxamide

Zinc chloride (9 mg, 0.067 mmol) was added to a stirring solution of5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(50 mg, 0.135 mmol) and (S)-2-amino-2-phenylethanol (93 mg, 0.675 mmol)in PhCl (3 mL) rt. It was subjected to two iterations of microwaveirradiation at 200° C. for 1 hr. The material was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (16 mg, 23%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.33 (1H,s), 7.94-8.00 (4H, m), 7.91 (1H, d, J=7.94 Hz), 7.64-7.73 (2H, m), 7.61(1H, t, J=7.78 Hz), 7.32-7.42 (6H, m), 7.26 (2H, t, J=8.55 Hz), 5.45(1H, t, J=9.16 Hz), 4.94 (1 H, t, J=9.31 Hz), 4.36 (1H, t, J=8.24 Hz),2.97 (3H, s). LC-MS retention time 1.76 min; m/z (MH+): 491. LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% MeOH/95% H₂O/10 mM ammonium bicarbonate, Solvent B=95%MeOH/5% H₂O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, R_(t)=18.32 min, purity=99%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 μm, R_(t)=18.10min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)benzofuran-3-carboxamide

DIEA (50 μL, 0.288 mmol) was added to Pd(Ph3P)₄ (6 mg, 4.79 μmol),-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (40 mg, 0.096 mmol),3-(5-methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid (29 mg, 0.144 mmol).Dioxane (1 mL) and water (200 μL) was added at rt. The reaction washeated to 90° C. overnight. The mixture was cooled and purified bypreparative reverse phase HPLC on a C18 column using a suitably bufferedH₂O/CH₃CN gradient, and concentrated to give the titled compound (16 mg,37%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.56 (1H, m), 8.24 (1H, s),7.98-8.05 (4H, m), 7.93 (1H, s), 7.79-7.83 (1H, m), 7.68-7.76 (2H, m),7.41 (2H, t, J=8.70 Hz), 2.87 (3H, d, J=4.58 Hz), 2.62 (3H, s). LC-MSretention time: 1.41 min; m/z (MH−): 426. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95%H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.96 min,purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,Rt=11.53 min, purity=94%.

6-(cyclopropanesulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Cyclopropanesulfonyl chloride (8 μL, 0.058 mmol) was added to a stirringsolution of6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide(20 mg, 0.038 mmol) in Pyridine (0.5 mL) at rt. It was allowed to stirfor 2 hours. The mixture was concentrated purified by preparativereverse phase HPLC on a C18 column using a suitably buffered H₂O/CH₃CNgradient, and concentrated to give the titled compound (17 mg, 70%). 1HNMR (500 MHz, CD₃OD) δ ppm 8.41 (1H, br. s.), 7.91-8.01 (3H, m),7.78-7.86 (2H, m), 7.61-7.71 (2H, m), 7.58 (1H, t, J=7.63 Hz), 7.41-7.49(2H, m), 7.24-7.33 (4H, m), 7.18 (1H, t, J=6.87 Hz), 2.94 (3H, s),2.34-2.43 (1H, m), 1.77 (6H, s), 0.80-1.03 (4H, m). LC-MS retentiontime: 1.53 min; m/z (MH+): 626. LC data was recorded on a ShimadzuLC-10AS liquid chromatograph equipped with a Waters XBridge 5u C184.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95%H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.40 min,purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,Rt=12.65 min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)benzofuran-3-carboxamide

DIEA (50 μL, 0.288 mmol) was added to Pd(Ph3P)₄ (6 mg, 4.79 μmol),2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (40 mg, 0.096 mmol),3-(5-methyl-1,3,4-oxadiazol-2-yl)phenylboronic acid (29 mg, 0.144 mmol).Dioxane (799 μL) and water (160 μL) was added at rt. The reaction washeated to 90° C. overnight. The mixture was cooled and purified by prepHPLC to give the titled compound (16 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆)ppm 8.49-8.56 (1H, m), 8.24 (1H, s), 7.98-8.05 (4 H, m), 7.93 (1H, s),7.79-7.83 (1H, m), 7.68-7.76 (2H, m), 7.41 (2H, t, J=8.70 Hz), 2.87 (3H,d, J=4.58 Hz), 2.62 (3H, s). LC-MS retention time: 1.41 min; m/z (MH−):426. LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AVUV-V is detector at a detector wave length of 220 nM. The elutionconditions employed a flow rate of 5 ml/min, a gradient of 100% solventA/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min,a hold time of 1 min, and an analysis time of 3 min where solvent A was5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5%H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determinedusing a Micromass Platform for LC in electrospray mode. Analytical HPLCmethod: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5%H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150mm, 3.5 m, R_(t)=12.96 min, purity=95%; Column: Waters Xbridge Phenylcolumn 4 6×150 mm, 3.5 m, R_(t)=11.53 min, purity=94%.

2-(4-fluorophenyl)-5-(3-(3-isopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-methylbenzofuran-3-carboxamide

Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry ofmethyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate(50 mg, 0.124 mmol) and (Z)—N′-hydroxyisobutyrimidamide (38 mg, 0.372mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwaveirradiation for 5 min at 160° C. The mixture was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d₆) d ppm 8.46-8.54(1H, m), 8.35 (1H, s), 8.11 (1H, d, J=7.78 Hz), 7.97-8.08 (3H, m),7.92-7.97 (1H, m), 7.73-7.84 (3H, m), 7.40 (2H, t, J=8.91 Hz), 3.12-3.23(1H, m), 2.87 (3H, d, J=4.52 Hz), 1.36 (6H, d, J=7.03 Hz). LC-MSretention time: 1.80 min; m/z (MH+): 456. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=16.33 min,purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,R_(t)=13.72 min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl)benzofuran-3-carboxamide

Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry ofmethyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate(50 mg, 0.124 mmol) and (Z)—N′-hydroxybenzimidamide (51 mg, 0.372 mmol)in EtOH (2.5 mL) at rt. The mixture was subjected to microwaveirradiation for 5 min at 160° C. The mixture was concentrated andpurified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (8.7 mg, 14%). 1H NMR (400 MHz, DMSO-d₆) d ppm 8.49-8.56(1H, m), 8.44-8.49 (1H, m), 8.19-8.25 (1H, m), 8.13-8.18 (2H, m),8.07-8.12 (1H, m), 8.00-8.07 (2H, m), 7.98 (1H, s), 7.76-7.86 (3H, m),7.59-7.68 (3H, m), 7.41 (2H, t, J=8.91 Hz), 2.88 (3H, d, J=4.77 Hz).LC-MS retention time: 1.94 min; m/z (MH+): 490. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=17.39 min,purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,R_(t)=14.58 min, purity=98%.

2-(4-fluorophenyl)-N-methyl-5-(3-(4-phenyl-1H-imidazol-2-yl)phenyl)benzofuran-3-carboxamide

2-oxo-2-phenylacetaldehyde hydrate (10 mg, 0.066 mmol) in MeOH (1 mL)was added to a stirring solution of2-(4-fluorophenyl)-5-(3-formylphenyl)-N-methylbenzofuran-3-carboxamide(20 mg, 0.054 mmol) and ammonium acetate (25 mg, 0.324 mmol) in MeOH (1mL) at rt. It was allowed to stir overnight. The reaction was purifiedby preparative reverse phase HPLC on a C18 column using a suitablybuffered H₂O/CH₃CN gradient, and concentrated to give the titledcompound (6.5 mg, 24%). 1H NMR (500 MHz, DMSO-d₆) ppm 12.82 (1H, br.s.), 8.51-8.58 (1H, m), 8.35 (1H, br. s.), 7.98-8.07 (3H, m), 7.93-7.97(1H, m), 7.76-7.90 (4H, m), 7.72 (1H, d, J=7.63 Hz), 7.60 (1H, t, J=7.78Hz), 7.36-7.45 (4H, m), 7.19-7.29 (1H, m), 2.88 (3H, d, J=4.58 Hz).LC-MS retention time: 1.57 min; m/z (MH+): 488. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6 150 mm, 3.5 mm, R_(t)=9.54 min,purity=96%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,R_(t)=10.41 min, purity=97%.

5-(3-(1-(1,3,4-thiadiazol-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

DIEA (44 μL, 0.253 mmol) was added to a stirring solution of2434244-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid (40 mg, 0.084 mmol), 1,3,4-thiadiazol-2-amine (17.05 mg, 0.169mmol) in DMF (843 μL) at rt. NaH (17 mg, 0.422 mmol) was added, and theslurry became a clear solution after 10 min. It was allowed to stirovernight. The reaction was purified by preparative reverse phase HPLCon a C18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (22 mg, 45%). 1H NMR (500 MHz,DMSO-d₆) δ ppm 12.44 (1H, br. s.), 9.14 (1H, br. s.), 8.78 (1H, br. s.),8.47-8.57 (1H, m), 8.30 (1H, s), 7.97-8.04 (2H, m), 7.88-7.95 (3H, m),7.75-7.84 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.41 (2H, t), 2.86 (3H, d,J=4.88 Hz), 1.57 (6H, s). LC-MS retention time: 1.57 min; m/z (MH+):488. LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 ml/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent Bwas 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode. Additional HPLCmethod: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5%H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150mm, 3.5 mm, R_(t)=11.23 min, purity=97%; Column: Waters Xbridge Phenylcolumn 4 6×150 mm, 3.5 mm, R_(t)=10.56 min, purity=96%.

5-(3-(1H-pyrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Cesium carbonate (234 mg, 0.719 mmol) was added to Pd(Ph3P)4 (20.77 mg,0.018 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (150 mg, 0.359 mmol),5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(146 mg, 0.539 mmol). Dioxane (3 mL) and water (599 μL) was added at rt.The reaction was heated to 90° C. overnight. The mixture was dilutedwith EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phasewas dried over Na2SO4, filtered and concentrated and purified bytrituration with Et2O to give the titled compound (140 mg, 92%). 1H NMR(400 MHz, DMSO-d₆) d ppm 13.40 (1H, br. s.), 12.91 (1H, br. s.),8.45-8.55 (1H, m), 8.13 (1H, s), 7.97-8.08 (2H, m), 7.85-7.95 (1H, m),7.73-7.85 (4H, m), 7.59-7.67 (1H, m), 7.49-7.58 (1H, m), 7.35-7.45 (2H,m), 6.84 (1H, br. s.), 2.87 (3H, d, J=4.52 Hz). LC-MS retention time:1.41 min; m/z (MH+): 412. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode. Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA,Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=11.86 min, purity=97%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, R_(t)=10.97min, purity=99%.

5-(3-(1-benzyl-1H-pyrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

(Bromomethyl)benzene (17 mg, 0.097 mmol) was added to a stirringsolution of Na2CO3 (11 mg, 0.097 mmol) and5-(3-(1H-pyrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(20 mg, 0.049 mmol) in DMF (486 μL) at 100° C. It was allowed to stirovernight, filtered and purified by preparative reverse phase HPLC on aC18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (8.6 mg, 35%). 1H NMR (500 MHz,DMSO-d₆) δ ppm 8.49-8.57 (1H, m), 8.06-8.11 (1 H, m), 7.98-8.04 (2H, m),7.92 (1H, d, J=2.44 Hz), 7.86-7.89 (1H, m), 7.75-7.83 (2H, m), 7.69-7.75(1H, m), 7.63 (1H, d, J=8.24 Hz), 7.51 (1H, t, J=7.63 Hz), 7.34-7.43(4H, m), 7.27-7.32 (3H, m), 6.89 (1H, d, J=2.44 Hz), 5.41 (2H, s), 2.86(3H, d, J=4.58 Hz). LC-MS retention time: 2.00 min; m/z (MH+): 502. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode. Additional HPLC method: SolventA=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm,R_(t)=15.47 min, purity=99%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 mm, R_(t)=13.77 min, purity=100%.

2-(4-fluorophenyl)-N-methyl-5-(3-(2-methyl-1-(5-methyl-1H-pyrazol-3-ylamino)-1-oxopropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

DIEA (28 μL, 0.158 mmol) was added to a stirring solution of2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid (25 mg, 0.053 mmol), 5-methyl-1H-pyrazol-3-amine (11 mg, 0.105mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11mg, 0.263 mmol) was added and the reaction was allowed to stirovernight. The mixture was treated with a drop of MeOH and was purifiedby preparative reverse phase HPLC on a C18 column using a suitablybuffered H₂O/CH₃CN gradient, and concentrated to give the titledcompound (6.4 mg, 21%). 1H NMR (500 MHz, DMSO-d₆) d ppm 11.90 (1H, br.s.), 9.84 (1H, br. s.), 8.51-8.56 (1H, m), 8.41 (1H, br. s.), 8.23-8.28(1H, m), 7.98-8.03 (2H, m), 7.86-7.93 (3H, m), 7.76-7.83 (2H, m), 7.59(1H, t, J=7.63 Hz), 7.37-7.43 (2H, m), 6.28 (1H, br. s.), 2.87 (3H, d,J=4.88 Hz), 2.17 (3H, s), 1.54 (6 H, s). LC-MS retention time: 1.56 min;m/z (MH+): 554. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent Bwas 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode. Additional HPLCmethod: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5%H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150mm, 3.5 mm, R_(t)=10.47 min, purity=97%; Column: Waters Xbridge Phenylcolumn 4 6×150 mm, 3.5 mm, R_(t)=9.58 min, purity=96%.

2-(4-fluorophenyl)-N-methyl-5-(3-(2-methyl-1-(3-methylisoxazol-5-ylamino)-1-oxopropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

DIEA (28 μL, 0.158 mmol) was added to a stirring solution of2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid (25 mg, 0.053 mmol), 3-methylisoxazol-5-amine (11 mg, 0.105 mmol)in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg,0.263 mmol) was added and the reaction was allowed to stir overnight.The mixture was treated with a drop of MeOH and was purified bypreparative reverse phase HPLC on a C18 column using a suitably bufferedH₂O/CH₃CN gradient, and concentrated to give the titled compound (3.3mg, 11%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.18-8.24 (1H, m), 7.93-8.00(3H, m), 7.84-7.91 (2H, m), 7.65-7.74 (2H, m), 7.58 (1H, t, J=7.78 Hz),7.23-7.31 (2H, m), 2.98 (3H, s), 2.24 (3H, s), 1.65 (6H, s). LC-MSretention time: 1.69 min; m/z (MH+): 555. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=12.09min, purity=100%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5mm, R_(t)=11.18 min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(2-methyl-1-(5-methylisoxazol-3-ylamino)-1-oxopropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

DIEA (28 μL, 0.158 mmol) was added to a stirring solution of2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid (25 mg, 0.053 mmol), 5-methylisoxazol-3-amine (11 mg, 0.105 mmol)in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg,0.263 mmol) was added and the reaction was allowed to stir overnight.The mixture was treated with a drop of MeOH and was purified bypreparative reverse phase HPLC on a C18 column using a suitably bufferedH₂O/CH₃CN gradient, and concentrated to give the titled compound (2.8mg, 9%). 1H NMR (500 MHz, CD₃OD) δ ppm 8.17-8.25 (1H, m), 7.92-8.00 (3H,m), 7.83-7.91 (2H, m), 7.66-7.76 (2H, m), 7.58 (1H, t, J=7.78 Hz), 7.27(2H, t, J=8.85 Hz), 6.63 (1H, s), 2.98 (3H, s), 2.39 (3H, s), 1.65 (6H,s). LC-MS retention time: 1.69 min; m/z (MH+): 555. LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode. Additional HPLC method: SolventA=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm,R_(t)=12.20 min, purity=95%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 mm, R_(t)=11.30 min, purity=90%.

5-(3-(1-(1,2,4-triazin-3-ylamino)-2-methyl-1-oxopropan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

DIEA (28 μL, 0.158 mmol) was added to a stirring solution of2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid (25 mg, 0.053 mmol), 1,2,4-triazin-3-amine (11 mg, 0.105 mmol) inDMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263mmol) was added and the reaction was allowed to stir overnight. Themixture was treated with a drop of MeOH and was purified by preparativereverse phase HPLC on a C18 column using a suitably buffered H₂O/CH₃CNgradient, and concentrated to give the titled compound (7.4 mg, 25%). 1HNMR (500 MHz, CD₃OD) δ ppm 8.58-8.63 (1H, m), 8.22-8.26 (1 H, m),7.93-8.00 (3H, m), 7.85-7.93 (2H, m), 7.66-7.75 (2H, m), 7.59 (1H, t,J=7.63 Hz), 7.27 (2H, t, J=8.85 Hz), 2.98 (3H, s), 1.72 (6H, s). LC-MSretention time: 1.56 min; m/z (MH+): 553. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=9.65 min,purity=97%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,R_(t)=9.58 min, purity=97%.

2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

Oxalyl chloride (22 μL, 0.250 mmol) was added to a stirring solution of2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxylicacid (50 mg, 0.083 mmol) in DCE (832 up at rt. DMF (3 μL, 0.042 mmol)was added. The mixture was allowed to stir for 30 min, concentrated anddiluted with THF. DIEA (59 μL, 0.333 mmol) and methanamine (208 μL,0.416 mmol, 2M in THF) was added. It was allowed to stir overnight. Themixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl.The organic phase was dried over Na2SO4, filtered and concentrated andwas purified by preparative reverse phase HPLC on a C18 column using asuitably buffered H₂O/CH₃CN gradient, and concentrated to give thetitled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d₆) d ppm 8.46-8.56(1H, m), 8.36 (1H, s), 7.97-8.05 (3H, m), 7.94 (1H, s), 7.86 (1H, d,J=7.78 Hz), 7.59-7.67 (2H, m), 7.53 (1H, t, J=7.65 Hz), 7.35-7.42 (4H,m), 7.29 (2H, t, J=7.78 Hz), 7.17 (1H, t, J=7.28 Hz), 3.06 (3H, s), 3.01(3H, s), 2.82 (3H, d, J=4.52 Hz), 1.69 (6H, s). LC-MS retention time:1.51 min; m/z (MH+): 614. LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode. Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA,Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column:Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=12.89 min, purity=92%;Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, R_(t)=12.11min, purity=91%.

5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Tert-butylamine (21 μL, 0.195 mmol) was added to a stirring solution ofHATU (45 mg, 0.117 mmol), DIEA (41 μL, 0.234 mmol), and3-(6-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (50 mg, 0.078 mmol) in DMF (780 μL) at rt. It was allowed to stirfor 1 hour. The mixture was diluted with EtOAc and washed with satNaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filteredand concentrated and was purified by preparative reverse phase HPLC on aC18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (11 mg, 23%). 1H NMR (500 MHz,CD₃OD) d ppm 8.04 (1H, br. s.), 7.94-8.02 (2H, m), 7.77-7.86 (2H, m),7.66-7.73 (2H, m), 7.49-7.59 (2 H, m), 7.24-7.34 (2H, m), 3.56-3.66 (1H,m), 3.35-3.43 (2H, m), 3.27 (3H, s), 2.94 (3H, s), 2.78-2.87 (1H, m),1.47 (9H, s). LC-MS retention time: 1.57 min; m/z (MH+): 582. LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5mm, R_(t)=10.88 min, purity=97%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 mm, R_(t)=10.27 min, purity=96%.

ethyl2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)phenyl)-4-methyl-1H-imidazole-5-carboxylate

Cesium carbonate (234 mg, 0.719 mmol) was added to Pd(Ph3P)₄ (27.7 mg,0.024 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (200 mg, 0.479 mmol), ethyl4-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole-5-carboxylate(171 mg, 0.479 mmol). Dioxane (4 mL) and water (800 μL) was added at rt.The reaction was heated to 90° C. overnight. The mixture was dilutedwith ethyl acetate and washed with sat NaHCO3, and sat NaCl. The organicphase was dried over Na2SO4, filtered and concentrated and was purifiedon silica gel (Biotage, EtOAc/hexanes gradient, fraction collection atλ=254 nm) to give the titled compound (6.8 mg, 3%). 1H NMR (500 MHz,DMSO-d₆) d ppm 13.16 (0.34H, s), 12.96 (0.66H, s), 8.54 (1H, q, J=4.48Hz), 8.50 (0.32H, s), 8.24 (0.68H, s), 8.10 (0.31H, d, J=7.93 Hz),7.97-8.04 (2H, m), 7.89-7.97 (2H, m), 7.79-7.84 (1.35H, m), 7.70-7.79(2H, m), 7.54-7.63 (1H, m), 7.37-7.44 (2H, m), 4.33 (0.65H, q, J=7.22Hz), 4.25 (1.42H, q, J=7.22 Hz), 2.87 (3H, d, J=4.88 Hz), 2.55 (2H, s),2.45 (1H, s), 1.34 (1H, t, J=7.02 Hz), 1.31 (2H, t, J=7.17 Hz). LC-MSretention time: 1.46 min; m/z (MH+): 498. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5uC18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, R_(t)=9.90 min,purity=99%.

2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

1-(pyridin-2-yl)cyclopropanamine dihydrochloride (24 mg, 0.114 mmol) wasadded to a stirring solution of HATU (54 mg, 0.142 mmol), DIEA (50 μL,0.285 mmol), and3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (50 mg, 0.095 mmol) in DMF (950 μL) at rt. It was allowed to stirfor 1 hour. The mixture was diluted with EtOAc and washed with satNaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filteredand concentrated and was purified by preparative reverse phase HPLC on aC18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (20 mg, 32%). 1H NMR (500 MHz,DMSO-d₆) d ppm 9.20 (1H, s), 8.49-8.57 (1H, m), 8.45 (1H, d, J=3.97 Hz),7.97-8.05 (3H, m), 7.96 (1H, s), 7.94 (1H, d, J=7.93 Hz), 7.80 (1H, d,J=7.93 Hz), 7.64-7.69 (1H, m), 7.63 (1H, s), 7.56 (1H, t, J=7.63 Hz),7.37-7.47 (3H, m), 7.15 (1H, dd, J=6.41, 4.88 Hz), 4.91 (1H, br. s.),3.51-3.60 (1H, m), 3.22 (3H, s), 2.89-2.98 (3H, m), 2.81 (3H, d),1.50-1.60 (2H, m), 1.23-1.33 (2H, m). LC-MS retention time: 1.37 min;m/z (MH+): 643. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-V is detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, SolventB=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: WatersSunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=7.17 min, purity=98%; Column:Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, R_(t)=7.89 min,purity=99%.

2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

1-phenylcyclopropanamine hydrochloride (16 mg, 0.091 mmol) was added toa stirring solution of HATU (43 mg, 0.114 mmol), DIEA (40 μL, 0.228mmol), and3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (40 mg, 0.076 mmol) in DMF (760 μL) at rt. It was allowed to stirfor 1 hour. The mixture was diluted with EtOAc and washed with satNaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filteredand concentrated and was purified by preparative reverse phase HPLC on aC18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (22 mg, 44%). 1H NMR (500 MHz,DMSO-d₆) d ppm 9.12 (1H, s), 8.49-8.56 (1H, m), 7.97-8.05 (3H, m), 7.95(1H, s), 7.90 (1H, d, J=7.93 Hz), 7.78 (1H, d, J=7.93 Hz), 7.62 (1H, s),7.54 (1H, t, J=7.78 Hz), 7.37-7.46 (2H, m), 7.28 (2H, t, J=7.63 Hz),7.19-7.24 (2H, m), 7.15 (1H, t, J=7.32 Hz), 4.90 (1H, t, J=5.19 Hz),3.50-3.58 (1H, m), 3.25-3.28 (1H, m), 3.21 (3H, s), 2.88-2.96 (2H, m),2.82 (3H, d, J=4.58 Hz), 1.22-1.32 (4H, m). LC-MS retention time: 1.57min; m/z (MH+): 642. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, SolventB=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: WatersSunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=11.28 min, purity=99%; Column:Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, R_(t)=10.86 min,purity=98%.

2-(4-fluorophenyl)-5-(3-(1-(4-fluorophenyl)cyclopropylcarbamoyl)phenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

1-(4-fluorophenyl)cyclopropanamine hydrochloride (22 mg, 0.114 mmol) wasadded to a stirring solution of HATU (54 mg, 0.142 mmol), DIEA (50 μL,0.285 mmol), and3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (50 mg, 0.095 mmol) in DMF (950 μL) at rt. It was allowed to stirfor 1 hour. The mixture was diluted with EtOAc and washed with satNaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filteredand concentrated and was purified by preparative reverse phase HPLC on aC18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (30 mg, 47%). 1H NMR (500 MHz,DMSO-d₆) d ppm 9.14 (1H, s), 8.49-8.55 (1H, m), 7.99-8.04 (2H, m),7.97-7.98 (1H, m), 7.95 (1H, s), 7.88 (1H, d, J=8.24 Hz), 7.78 (1H, d,J=7.93 Hz), 7.61 (1H, s), 7.53 (1H, t, J=7.78 Hz), 7.39-7.45 (2H, m),7.22-7.32 (2H, m), 7.05-7.13 (2H, m), 4.90 (1H, t, J=5.04 Hz), 3.50-3.58(1H, m), 3.24-3.28 (1H, m), 3.20 (3H, s), 2.93 (2H, br. s.), 2.81 (3H,d, J=4.58 Hz), 1.25 (4H, d, J=9.77 Hz). LC-MS retention time: 1.60 min;m/z (MH+): 660. LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm columnusing a SPD-10AV UV-V is detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.Additional HPLC method: Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, SolventB=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: WatersSunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=11.49 min, purity=99%; Column:Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, R_(t)=11.04 min,purity=99%.

2-(4-fluorophenyl)-5-(3-(2-(4-fluorophenyl)propan-2-ylcarbamoyl)phenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

2-(4-fluorophenyl)propan-2-amine (18 mg, 0.114 mmol) was added to astirring solution of HATU (54 mg, 0.142 mmol), DIEA (50 μL, 0.285 mmol),and 2-(4-fluorophenyl)propan-2-amine (18 mg, 0.114 mmol) in DMF (950 μL)at rt. It was allowed to stir for 1 hour. The mixture was diluted withEtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase wasdried over Na2SO4, filtered and concentrated and was purified bypreparative reverse phase HPLC on a C18 column using a suitably bufferedH₂O/CH₃CN gradient, and concentrated to give the titled compound (18 mg,28%). 1H NMR (500 MHz, DMSO-d₆) d ppm 8.50-8.56 (1H, m), 8.31 (1H, s),7.98-8.05 (3H, m), 7.96 (1H, s), 7.83 (1H, d, J=7.63 Hz), 7.73 (1 H, d,J=7.63 Hz), 7.62 (1H, s), 7.53 (1H, t, J=7.78 Hz), 7.38-7.47 (4H, m),7.09 (2 H, t, J=8.85 Hz), 4.90 (1H, t, J=5.19 Hz), 3.50-3.58 (1H, m),3.26-3.29 (1H, m), 3.23 (3H, s), 2.87-2.93 (2H, m), 2.82 (3H, d, J=4.58Hz), 1.67 (6H, s). LC-MS retention time: 1.66 min; m/z (MH+): 662. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode. Additional HPLC method:Solvent A=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1%TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5mm, R_(t)=12.11 min, purity=99%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 mm, Rt=11.48 min, purity=100%.

5-(3-(1-(4-chlorophenyl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

1-(4-chlorophenyl)cyclopropanamine hydrochloride (25 mg, 0.123 mmol) wasadded to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL,0.308 mmol), and3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, andsat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated and was purified by preparative reverse phase HPLC on a C18column using a suitably buffered H₂O/CH₃CN gradient, and concentrated togive the titled compound (8 mg, 14%). 1H NMR (500 MHz, DMSO-d₆) d ppm9.37 (1H, s), 8.46-8.55 (1H, m), 8.22 (1H, s), 7.95-8.05 (2H, m),7.86-7.95 (3H, m), 7.74-7.83 (2H, m), 7.59 (1H, t, J=7.63 Hz), 7.38-7.44(2H, m), 7.30-7.36 (2H, m), 7.20-7.28 (2H, m), 2.86 (3H, d, J=4.58 Hz),1.26-1.36 (4H, m). LC-MS retention time: 1.92 min; m/z (MH+): 539. LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90%MeOH/0.1% trifluoroacetic acid. MS data was determined using a MicromassPlatform for LC in electrospray mode. Additional HPLC method: SolventA=5% CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start% B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, FlowRate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm,R_(t)=14.56 min, purity=99%; Column: Waters Xbridge Phenyl column 46×150 mm, 3.5 mm, R_(t)=13.20 min, purity=97%.

5-(3-(2-(4-chlorophenyl)propan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

2-(4-chlorophenyl)propan-2-amine (21 mg, 0.123 mmol) was added to astirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL, 0.308 mmol),and 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3,and sat NaCl. The organic phase was dried over Na2SO4, filtered andconcentrated and was purified by preparative reverse phase HPLC on a C18column using a suitably buffered H₂O/CH₃CN gradient, and concentrated togive the titled compound (32 mg, 57%). 1H NMR (500 MHz, DMSO-d₆) d ppm8.64 (1H, s), 8.47-8.55 (1H, m), 8.14 (1H, s), 7.99-8.04 (2H, m), 7.92(1H, s), 7.74-7.89 (4H, m), 7.57 (1H, t, J=7.78 Hz), 7.37-7.45 (4H, m),7.34 (2H, d, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz), 1.69 (6H, s). LC-MSretention time: 1.95 min; m/z (MH+): 541. LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1%trifluoroacetic acid. MS data was determined using a Micromass Platformfor LC in electrospray mode. Additional HPLC method: Solvent A=5%CH₃CN/95% H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start %B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=15.18min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5mm, R_(t)=13.66 min, purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(2-(pyridin-4-yl)propan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

2-(pyridin-4-yl)propan-2-amine dihydrochloride (26 mg, 0.123 mmol) wasadded to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL,0.308 mmol), and3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1hour. The reaction was purified by preparative reverse phase HPLC on aC18 column using a suitably buffered H₂O/CH₃CN gradient, andconcentrated to give the titled compound (15 mg, 27%). 1H NMR (500 MHz,DMSO-d₆) d ppm 8.73 (1H, s), 8.50-8.55 (1H, m), 8.48 (2H, dd, J=4.58,1.53 Hz), 8.16 (1H, s), 7.97-8.04 (2H, m), 7.91-7.94 (1H, m), 7.88 (1H,d, J=7.63 Hz), 7.85 (1H, d, J=7.93 Hz), 7.75-7.82 (2H, m), 7.58 (1H, t,J=7.63 Hz), 7.36-7.43 (4H, m), 2.86 (3H, d, J=4.58 Hz), 1.68 (6H, s).LC-MS retention time: 1.59 min; m/z (MH+): 508. LC data was recorded ona Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 2 min, a hold time of 1 min, and ananalysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. Additional HPLC method: Solvent A=5% CH₃CN/95%H₂O/0.1% TFA, Solvent B=95% CH₃CN/5% H₂O/0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min.Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, R_(t)=8.60 min,purity=95%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm,R_(t)=9.26 min, purity=96%.

2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carbothioamide

The reaction was run in two batches and combined for workup. In thefirst batch, Lawesson's reagent (27 mg, 0.067 mmol) was added to asolution of2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide(35 mg, 0.086 mmol) in THF (1.2 mL). The reaction was stirred at r.t.for 2 h, at which point additional Lawesson's reagent (8 mg, 0.020 mmol)was added. In the second batch, Lawesson's reagent (129 mg, 0.32 mmol)was added to a solution of2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carboxamide(125 mg, 0.31 mmol) in THF (3 mL) was stirred at r.t. for 1.5 h. The twobatches were then combined and partitioned between EtOAc (50 mL) andwater (10 mL). The organic phase was washed with sat'd NaHCO₃ and brine,dried over Na₂SO₄, filtered, and concentrated to give a yellow oil. Theresidue was purified by silica gel chromatography (Biotage 25+S silicagel cartridge, gradient elution: 20% to 80% EtOAc/hexanes over 20 columnvolumes, fraction collection at λ=320 nm) to give 48 mg (29% yield) ofthe title compound. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.76-7.87 (m, 2H) 7.71(d, J=5.86 Hz, 2H) 7.53 (br. s., 1H) 7.13-7.23 (m, 2H) 6.97 (s, 1H) 6.90(br. s., 1H) 4.74 (dt, J=12.08, 6.04 Hz, 1H) 2.93 (s, 3H) 1.40 (d,J=6.22 Hz, 6H). LC/MS was performed by using Shimadzu-VP instrument withUV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5%CH₃CN/95% H₂O/0.1% NH₄OAc, solvent B=95% CH₃CN/5% H₂O/0.1% NH₄OAc, start% B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC R_(t)=1.39 min, (ES+)m/z (MH⁺)=423.

N-(2-(4-fluorophenyl)-5-isopropoxy-3-(thiazol-2-yl)benzofuran-6-yl)methanesulfonamide

Chloroacetaldehyde (50% solution in water, 100 μL, 0.79 mmol) was addedto a stirred suspension of the intermediate2-(4-fluorophenyl)-5-isopropoxy-6-(methylsulfonamido)benzofuran-3-carbothioamide(48 mg, 0.11 mmol) in ethanol (1.5 mL), and the reaction was brought toreflux (100° C. oil bath temp). After 4 h, additional chloroacetaldehydesolution (200 μL, 1.6 mmol) was added and heating was continuedovernight. The reaction was cooled to r.t., diluted with EtOAc (75 mL),washed with water (10 mL), sat'd NaHCO₃ (2×5 mL), and brine, dried overNa₂SO₄, filtered, and concentrated to give a brown oil. The residue waspurified on silica gel (Biotage 12+M column, gradient elution 10% to 40%EtOAc/hexanes over 20 column volumes, fraction collection at λ=320 nm)to give a colorless oil, 38 mg (75% yield). ¹H NMR (300 MHz, CDCl₃) δppm 7.96 (d, J=3.29 Hz, 1H) 7.73-7.86 (m, 3H) 7.56 (s, 1H) 7.37 (d,J=3.29 Hz, 1H) 7.07-7.19 (m, 2H) 6.98 (s, 1H) 4.73 (spt, J=6.04 Hz, 1H)2.96 (s, 3H) 1.40 (d, J=5.86 Hz, 7H). An analytically pure sample wasobtained by precipitation from Et₂O/hexanes to give a yellow ppt., whichwas triturated with Et₂O and air dried. LC/MS was performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.LC/MS method: solvent A=5% CH₃CN/95% H₂O/0.1% NH₄OAc, solvent B=95%CH₃CN/5% H₂O/0.1% NH₄OAc, start % B=0, final % B=100, gradient time=2min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm4.6×50 mm; HPLC R_(t)=1.69 min, (ES+) m/z (MH⁺)=447. Analytical HPLCwere performed using a Shimadzu-VP instrument with UV detection at 220nm and 254 nm. Analytical HPLC method: solvent A=5% CH₃CN/95% H₂O/0.1%TFA, solvent B=95% CH₃CN/5% H₂O/0.1% TFA, start % B=10, final % B=100,gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column:Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, R_(t)=14.74 min, purity=97%;column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, R_(t)=12.86 min,purity=98%.

2-(4-fluorophenyl)-N-methyl-5-(3-(methylsulfonylcarbamoyl)phenyl)benzofuran-3-carboxamide

In a 1 dram vial with stir bar were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg,0.14 mmol), and methanesulfonamide (25 mg, 0.26 mmol). DMF (0.5 mL) wasadded, the vial was capped, and the reaction was stirred at r.t.overnight. The reaction was filtered, purified by prep HPLC, andconcentrated to give 30 mg (72% yield) of the title compound as a whitepowder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.36 (br. s., 1H) 8.53 (d,J=4.58 Hz, 1H) 8.27 (s, 1H) 7.97-8.05 (m, 2H) 7.84-7.96 (m, 3H)7.77-7.82 (m, 1H) 7.71-7.76 (m, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.40 (t,J=8.85 Hz, 2H) 3.17 (s, 3H) 2.86 (d, J=4.58 Hz, 3H). LC/MS was performedby using Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, solventB=90% CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100, gradienttime=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5μm 4.6×50 mm; HPLC R_(t)=1.56 min, (ES+) m/z (MH⁺)=467. Analytical HPLCwere performed using a Shimadzu-VP instrument with UV detection at 220nm and 254 nm. Analytical HPLC method: solvent A=5% CH₃OH/95% H₂O/10 mMNH₄HCO₃, solvent B=95% CH₃OH/5% H₂O/10 mM NH₄HCO₃, start % B=10, final %B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min.Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=11.93 min, purity=100%;column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, R_(t)=13.97 min,purity=99%.

5-(3-(tert-butylsulfonylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

In a 1 dram vial with stir bar were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg,0.14 mmol), and tert-butylsulfonamide (37 mg, 0.27 mmol).1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial wascapped, and the reaction was stirred at r.t. overnight. The reaction wasconcentrated, filtered, purified by prep HPLC, and concentrated on aspeedvac to give 14 mg (31% yield) of the title compound as a whitepowder. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.12 (s, 1H) 7.97 (s, 1H) 7.91(dd, J=8.55, 5.19 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.79 (d, J=7.32 Hz,1H) 7.46-7.59 (m, 3H) 7.19 (t, J=8.55 Hz, 2H) 6.04 (br. s., 1H) 2.99 (d,J=4.58 Hz, 3H) 1.54 (s, 9H). LC/MS was performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. LC/MSmethod: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, solvent B=90% CH₃CN/10%H₂O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stoptime=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLCR_(t)=1.71 min, (ES+) m/z (MH⁺)=509. Analytical HPLC were performedusing a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: solvent A=5% CH₃OH/95% H₂O/10 mM NH₄HCO₃,solvent B=95% CH₃OH/5% H₂O/10 mM NH₄HCO₃, start % B=10, final % B=100,gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column:Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=16.49 min, purity=100%; column:Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, R_(t)=15.35 min, purity=100%.

2-(4-fluorophenyl)-N-methyl-5-(3-(phenylsulfonylcarbamoyl)phenyl)benzofuran-3-carboxamide

In a 1 dram vial with stir bar were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg,0.14 mmol), and benzenesulfonamide (43 mg, 0.27 mmol).1,2-Dichloroethane (1 mL) and DMF (0.3 mL) were added, the vial wascapped, and the suspension was stirred at r.t. overnight, over whichtime the solids dissolved. The reaction was concentrated, filtered,purified by prep HPLC, and concentrated to give 32 mg (67% yield) of thetitle compound as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.78(br. s., 1H) 8.52 (q, J=4.48 Hz, 1H) 8.24 (s, 1H) 7.97-8.06 (m, 4H)7.90-7.97 (m, 2H) 7.85 (d, J=7.94 Hz, 1H) 7.74-7.81 (m, 2H) 7.66-7.73(m, 1H) 7.63 (t, J=7.63 Hz, 2H) 7.58 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85Hz, 2H) 2.87 (d, J=4.58 Hz, 3H). LC/MS was performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, solvent B=90%CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min,stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm;HPLC R_(t)=1.77 min, (ES+) m/z (MH⁺)=529. Analytical HPLC were performedusing a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: solvent A=5% CH₃OH/95% H₂O/10 mM NH₄HCO₃,solvent B=95% CH₃OH/5% H₂O/10 mM NH₄HCO₃, start % B=10, final % B=100,gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column:Phenomenex Gemini C18, 4.6 mm, 3 μm, R_(t)=15.70 min, purity=100%;column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, R_(t)=14.90 min,purity=99%.

2-(4-fluorophenyl)-N-methyl-5-(3-(methyhphenylsulfonyl)carbamoyl)phenyl)benzofuran-3-carboxamide

In a 1 dram vial with stir bar were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg,0.14 mmol), and N-methylbenzenesulfonamide (50 μL, 0.26 mmol).1,2-Dichloroethane (0.5 mL) and DMF (0.5 mL) were added, the vial wascapped, and the reaction was stirred at r.t. overnight. The reaction wasfiltered, purified by prep HPLC, and concentrated on a speedvac to give27 mg (55% yield) of the title compound as a white powder. ¹H NMR (500MHz, CDCl₃) δ ppm 7.91-8.02 (m, 5H) 7.75-7.82 (m, 2H) 7.65 (t, J=7.48Hz, 1H) 7.47-7.60 (m, 6H) 7.15-7.24 (m, 2H) 5.91 (d, J=4.27 Hz, 1H) 3.36(s, 3H) 3.04 (d, J=4.88 Hz, 3H). LC/MS was performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, Solvent B=90%CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min,stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm;HPLC R_(t)=1.89 min, (ES+) m/z (MH⁺)=543. Analytical HPLC were performedusing a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: solvent A=5% CH₃OH/95% H₂O/10 mM NH₄HCO₃,solvent B=95% CH₃OH/5% H₂O/10 mM NH₄HCO₃, start % B=10, final % B=100,gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column:Phenomenex Gemini C18, 4.6 mm, 3 μm, R_(t)=17.42 min, purity=92%;column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, R_(t)=17.86 min,purity>90%.

5-(3-(1-(cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

In a 7 mL scintillation vial were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(30 mg, 0.077 mmol),1-amino-N-(cyclopropylsulfonyl)cyclopropanecarboxamide hydrochloride (20mg, 0.083 mmol), and HATU (40 mg, 0.10 mmol). DMF (0.4 mL) and DIPEA(0.1 mL, 0.57 mmol) were added, the vial was capped, and the solutionwas stirred at r.t. for 45 min. The reaction was diluted with MeOH,filtered, purified by prep HPLC, and the collected fractions wereconcentrated on a speedvac to afford the title compound (23 mg, 52%yield) as a white powder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.99 (br. s.,1H) 8.53 (q, J=4.78 Hz, 1H) 8.25 (br. s., 1H) 8.00 (dd, J=8.85, 5.49 Hz,2H) 7.93 (s, 1H) 7.89 (t, J=7.78 Hz, 2H) 7.72-7.83 (m, 2H) 7.58 (t,J=7.48 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 7.07 (br. s., 1H) 2.89-2.98 (m,1H) 2.87 (d, J=4.58 Hz, 3H) 1.35-1.56 (m, 2H) 0.77-1.28 (m, 6H). LC/MSwas performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1%TFA, solvent B=90% CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100,gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column:Sunfire C18 5 μm 4.6×50 mm; HPLC R_(t)=1.59 min, (ES+) m/z (MH⁺)=576.Analytical HPLC were performed using a Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5%CH₃OH/95% H₂O/10 mM NH₄HCO₃, solvent B=95% CH₃OH/5% H₂O/10 mM NH₄HCO₃,start % B=10, final % B=100, gradient time=15 min, stop time=18 min,flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm,R_(t)=15.39 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm,3.5 μm, R_(t)=14.50 min, purity=100%.

5-(3-(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

In a 7 mL scintillation vial were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(30 mg, 0.077 mmol),(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide4-methylbenzenesulfonate (30 mg, 0.075 mmol), and HATU (40 mg, 0.10mmol). DMF (0.4 mL) and DIPEA (0.1 mL, 0.57 mmol) were added, the vialwas capped, and the solution was stirred at r.t. for 45 min. Thereaction was diluted with MeOH, filtered, purified by prep HPLC, and thecollected fractions were concentrated on a speedvac to afford the titlecompound (25 mg, 54% yield) as a white powder. ¹H NMR (500 MHz, CDCl₃) δppm 8.01 (s, 1H) 7.97 (s, 1H) 7.88 (dd, J=8.85, 5.19 Hz, 2H) 7.80 (d,J=7.63 Hz, 1H) 7.74 (d, J=7.63 Hz, 1H) 7.59 (br. s., 1H) 7.52 (s, 2H)7.48 (t, J=7.63 Hz, 1H) 7.18 (t, J=8.55 Hz, 2H) 6.00 (d, J=3.97 Hz, 1H)5.61-5.73 (m, 1H) 5.39 (d, J=17.09 Hz, 1H) 5.20 (d, J=10.99 Hz, 1H) 3.02(d, J=4.88 Hz, 3H) 2.91-2.99 (m, 1H) 2.34 (q, J=8.44 Hz, 1H) 2.05-2.09(m, 1H) 1.49 (dd, J=9.31, 5.95 Hz, 1H) 1.41 (dd, J=5.80, 4.58 Hz, 1H)1.30-1.35 (m, 1 H) 1.22-1.30 (m, 1H) 1.04-1.12 (m, 1H) 0.96-1.04 (m,1H). LC/MS was performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. LC/MS method: solvent A=10%CH₃CN/90% H₂O/0.1% TFA, solvent B=90% CH₃CN/10% H₂O/0.1% TFA, start %B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC R_(t)=1.73 min, (ES+)m/z (MH⁺)=602. Analytical HPLC were performed using a Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: solvent A=5% CH₃OH/95% H₂O/10 mM NH₄HCO₃, solvent B=95% CH₃OH/5%H₂O/10 mM NH₄HCO₃, start % B=10, final % B=100, gradient time=15 min,stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6mm, 3 μm, R_(t)=16.26 min, purity=100%; column: Waters Xbridge Phenyl4.6×150 mm, 3.5 μm, R_(t)=15.28 min, purity=100%.

2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid

HATU (450 mg, 1.18 mmol) was added to a suspension of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(400 mg, 1.03 mmol), methyl 2-amino-2-methylpropanoate hydrochloride(180 mg, 1.17 mmol), and DIPEA (0.6 mL, 3.4 mmol) in DCE (10 mL). After5 min, the solids had not dissolved. Add DMF (0.5 mL) and continuestirring the suspension at r.t. overnight. The reaction was thenconcentrated to give a thick suspension (DMF remained afterconcentration). Water and Et₂O were added and the flask swirled until afine grey suspension was formed. The ppt. was collected by filtration,rinsed with 1 N HCl, water, and ether, and air dried to afford 550 mg(110% yield) of the title compound as a grey solid. LC/MS was performedon a Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. LC/MS method: solvent A=5% CH₃CN/95% H₂O/10 mM NH₄OAc,solvent B=95% CH₃CN/5% H₂O/10 mM NH₄OAc, start % B=0, signal % B=100,gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column:XBridge C18 5 μm 4.6×50 mm; HPLC R_(t)=1.49 min, (ES+) m/z (MH⁺)=489. Toa suspension of the crude ester from above (˜0.1 mmol) in MeOH (7mL)/H₂O (2.1 mL) in a 20 mL scintillation vial with stir bar was added10 N NaOH soln. (0.4 mL, 4.00 mmol). The vial was capped, stirred atr.t. overnight, then quenched by pouring into 8 mL of 1 N HCl. A whiteppt. formed. The suspension was extracted with EtOAc, and the insolublegrey solid was collected by filtration and air dried (61 mg). Theorganic phase was washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give a white powder. This was triturated with Et₂O andcollected by filtration to give 360 mg of the white powder. Both cropsof ppt. were identical by LC/MS and were combined to give 421 mg (86%over two steps) of the title compound as an off-white powder. ¹H NMR(300 MHz, CD₃OD) δ ppm 8.59 (s, 1H) 8.50 (d, J=3.29 Hz, 1H) 8.10-8.16(m, 1H) 7.91-8.01 (m, 3H) 7.83 (dd, J=12.99, 7.87 Hz, 2H) 7.64-7.74 (m,2H) 7.56 (t, J=7.68 Hz, 1H) 7.27 (t, J=8.78 Hz, 2H) 2.95-3.02 (m, 3H)1.62 (s, 6H). LC/MS was performed on a Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. LC/MS method: solvent A=5%CH₃CN/95% H₂O/10 mM NH₄OAc, solvent B=95% CH₃CN/5% H₂O/10 mM NH₄OAc,start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flowrate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC R_(t)=1.06 min,(ES+) m/z (MH⁺)=475. Analytical HPLC were performed using a Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: solvent A=5% CH₃CN/95% H₂O/0.1% TFA, solvent B=95% CH₃CN/5%H₂O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stoptime=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm4.6×150 mm, R_(t)=10.91 min, purity=98%; column: Waters Xbridge Phenyl3.5 μm 4.6×150 mm, R_(t)=10.21 min, purity=98%.

5-(3-(1-(dimethylamino)-2-methyl-1-oxopropan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

A solution of dimethylamine in THF (2 molar, 0.10 mL, 0.20 mmol) wasadded to2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoicacid (17 mg, 0.036 mmol) and HATU (15 mg, 0.039 mmol) in a 1 dram vial.DMF (0.3 mL) was added, the vial was capped, and the homogeneoussolution was stirred at r.t. for 1 h, at which point DIPEA (50 μL, 0.29mmol) was added. Stirring was continued for 3 h, at which point thereaction was filtered and purified directly by prep HPLC. Concentrationof the collected fractions afforded the title compound as a white solid(13 mg, 71% yield). ¹H NMR (500 MHz, CD₃OD) δ ppm 8.09-8.17 (m, 1H)7.90-7.98 (m, 3H) 7.86 (d, J=7.94 Hz, 1H) 7.79-7.84 (m, 1H) 7.63-7.72(m, 2H) 7.57 (t, J=7.63 Hz, 1H) 7.20-7.32 (m, 2H) 3.14 (br. s., 3H) 2.98(s, 6H) 1.61 (s, 6H). LC/MS was performed on a Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. LC/MS method: solventA=5% CH₃CN/95% H₂O/10 mM NH₄OAc, solvent B=95% CH₃CN/5% H₂O/10 mMNH₄OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLCR_(t)=1.29 min, (ES+) m/z (MH⁺)=502. Analytical HPLC method: solventA=5% CH₃CN/95% H₂O/0.1% TFA, solvent B=95% CH₃CN/5% H₂O/0.1% TFA, start% B=10, final % B=100, gradient time=15 min, stop time=18 min, flowrate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm,R_(t)=14.80 min, purity=100%; column: Waters Xbridge Phenyl 3.5 μm4.6×150 mm, R_(t)=10.37 min, purity=100%.

5-(3-((cis)-2-(4-chlorophenyl)cyclopentylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

In a 1 dram vial were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(20 mg, 0.051 mmol), cis-2-(4-chlorophenyl)cyclopentanamine (14 mg,0.072 mmol), and HATU (31 mg, 0.082 mmol). DMF (0.4 mL) and DIPEA (50μL, 0.29 mmol) were added, and the vial was capped and stirred at r.t.for 2 h, then diluted with MeOH, filtered, and purify directly by prepHPLC. Concentration afforded the title compound (15 mg, 52% yield) as afluffy white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.47-8.59 (m, 1H)8.06 (d, J=8.85 Hz, 1H) 7.97-8.03 (m, 2H) 7.86 (d, J=1.83 Hz, 1H)7.75-7.82 (m, 2H) 7.68 (s, 1H) 7.65 (dd, J=8.55, 1.83 Hz, 1H) 7.45-7.53(m, 2H) 7.40 (t, J=8.85 Hz, 2H) 7.27 (s, 4H) 4.60-4.71 (m, J=7.67, 7.67,7.55, 7.32 Hz, 1H) 3.33-3.41 (m, 1H) 2.87 (d, J=4.58 Hz, 3H) 1.99-2.15(m, 3H) 1.89-1.98 (m, 1H) 1.72-1.82 (m, 1H) 1.57-1.71 (m, 1H). LC/MS wasperformed on a Shimadzu-VP instrument with UV detection at 220 nm andWaters Micromass. LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1% TFA,solvent B=90% CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100,gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column:Sunfire C18 5 μm 4.6×50 mm; HPLC R_(t)=2.02 min, (ES+) m/z (MH⁺)=567.Analytical HPLC method: solvent A=5% CH₃CN/95% H₂O/0.1% TFA, solventB=95% CH₃CN/5% H₂O/0.1% TFA, start % B=10, final % B=100, gradienttime=15 min, stop time=18 min, flow rate=1 ml/min. Column: WatersSunfire C-18, 3.5 μm 4.6×150 mm, R_(t)=15.42 min, purity=98%; column:Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, R_(t)=13.74 min, purity=97%.

5-(3-(biphenyl-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

In a 1 dram vial were combined3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(30 mg, 0.077 mmol), biphenyl-2-amine (17 mg, 0.10 mmol), and HATU (40mg, 0.105 mmol). DMF (0.4 mL) and DIPEA (50 μL, 0.29 mmol) were added,and the vial was capped and stirred at r.t. for overnight, then dilutedwith MeOH, filtered, and purified directly by prep HPLC. Concentrationafforded the title compound (17 mg, 41% yield) as a fluffy white solid.¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.96 (s, 1H) 8.53 (q, J=4.58 Hz, 1H)7.96-8.06 (m, 3H) 7.85-7.91 (m, 2H) 7.80 (d, J=8.55 Hz, 1H) 7.77 (d,J=7.32 Hz, 1H) 7.70 (dd, J=8.55, 1.83 Hz, 1H) 7.57-7.61 (m, 1H) 7.56 (d,J=6.10 Hz, 1H) 7.48 (d, J=7.32 Hz, 2H) 7.36-7.46 (m, 7H) 7.31 (t, J=7.48Hz, 1H) 2.87 (d, J=4.88 Hz, 3H). LC/MS was performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.LC/MS method: solvent A=10%

CH₃CN/90% H₂O/0.1% TFA, solvent B=90% CH₃CN/10% H₂O/0.1% TFA, start %B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC R_(t)=2.02 min, (ES+)m/z (MH⁺)=541. Analytical HPLC method: solvent A=5% CH₃CN/95% H₂O/0.1%TFA, solvent B=95% CH₃CN/5% H₂O/0.1% TFA, start % B=10, final % B=100,gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column:Waters Sunfire C-18, 3.5 μm 4.6×150 mm, R_(t)=15.37 min, purity=100%;column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, R_(t)=13.75 min,purity=100%.

5-(3-(benzyl(methyl)carbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

DIPEA (50 μL, 0.29 mmol) and N-methylbenzylamine (20 μL, 0.16 mmol) wereadded to a stirred suspension of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(20 mg, 0.051 mmol) and HATU (25 mg, 0.066 mmol) in DMF (0.5 mL) and thereaction was stirred at r.t. overnight. The reaction was then dilutedwith MeOH, filtered, purified by prep HPLC, and concentrated to give thetitle compound as a tan powder (12 mg, 47% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.50 (br. s., 1H) 8.01 (dd, J=8.39, 5.65 Hz, 2H)7.66-7.93 (m, 5H) 7.58 (br. s., 1H) 7.42-7.50 (m, 1H) 7.35-7.42 (m, 4H)7.31 (d, J=5.80 Hz, 1H) 7.23 (d, J=4.58 Hz, 1H) 4.72 (br. s., 1H) 4.54(br. s., 1H) 2.83-3.00 (m, 6H). LC/MS was performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. LC/MSmethod: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, solvent B=90% CH₃CN/10%H₂O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stoptime=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLCR_(t)=1.85 min, (ES+) m/z (MH⁺)=493. Analytical HPLC method: solventA=5% CH₃CN/95% H₂O/0.1% TFA, solvent B=95% CH₃CN/5% H₂O/0.1% TFA, start% B=10, final % B=100, gradient time=15 min, stop time=18 min, flowrate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm,R_(t)=16.26 min, purity=99%; column: Waters Xbridge Phenyl 3.5 μm4.6×150 mm, R_(t)=12.81 min, purity=98%.

2-(4-fluorophenyl)-5-(3-(isoindoline-2-carbonyl)phenyl)-N-methylbenzofuran-3-carboxamide

Isoindoline (20 μL, 0.18 mmol) was added to a stirred suspension of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight. Thereaction was then diluted with MeOH and an off-white ppt. formed. Theppt. was collected by filtration, triturated with MeOH, and air dried toafford the title compound (17 mg, 68% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 8.50 (q, J=4.58 Hz, 1H) 7.99-8.05 (m, 2H) 7.90-7.95 (m, 2H) 7.85(dt, J=6.10, 2.44 Hz, 1H) 7.77-7.81 (m, 1H) 7.73-7.77 (m, 1H) 7.58-7.64(m, 2H) 7.36-7.45 (m, 3H) 7.30-7.34 (m, 1H) 7.29 (s, 2H) 4.91 (s, 2H)4.84 (s, 2H) 2.86 (d, J=4.88 Hz, 3H). LC/MS was performed on aShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, solvent B=90%CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min,stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm;HPLC R_(t)=2.48 min, (ES+) m/z (MH⁺)=491. Analytical HPLC method:solvent A=5% CH₃CN/95% H₂O/0.1% TFA, solvent B=95% CH₃CN/5% H₂O/0.1%TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm,R_(t)=13.81 min, purity=100%; column: Waters Xbridge Phenyl 3.5 μm4.6×150 mm, R_(t)=13.81 min, purity=100%.

2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpyrrolidine-1-carbonyl)phenyl)benzofuran-3-carboxamide

2-Phenylpyrrolidine (20 mg, 0.14 mmol) was added to a stirred suspensionof 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight. Thereaction was then diluted with MeOH, filtered, and purified by prepHPLC. Concentration afforded the title compound (21 mg, 78% yield) as alight pink solid. ¹H NMR (˜3:2 ratio of amide rotamers, 500 MHz,DMSO-d₆) δ ppm 8.44-8.56 (m, 1H) 7.96-8.07 (m, 2H) 7.74-7.89 (m, 3H)7.56-7.67 (m, 2H) 7.30-7.45 (m, 5.4H) 7.16-7.29 (m, 2.6H) 7.09 (d,J=7.02 Hz, 1H) 5.19 (t, J=6.71 Hz, 0.6H) 4.98 (d, J=6.41 Hz, 0.4H)3.75-3.92 (m, 1.4H) 3.53-3.64 (m, 0.6H) 2.87 (m, 3H) 2.40 (dd, J=12.36,6.56 Hz, 0.6H) 2.30-2.38 (m, 0.4H) 1.73-1.92 (m, 3H). LC/MS wasperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1%TFA, solvent B=90% CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100,gradient time=3 min, stop time=4 min, flow rate=4 ml/min, column:Sunfire C18 5 μm 4.6×50 mm; HPLC R_(t)=1.86 min, (ES+) m/z (MH⁺)=519.Analytical HPLC method: solvent A=5% CH₃CN/95% H₂O/0.1% TFA, solventB=95% CH₃CN/5% H₂O/0.1% TFA, start % B=10, final % B=100, gradienttime=15 min, stop time=18 min, flow rate=1 ml/min. Column: WatersSunfire C-18, 3.5 μm 4.6×150 mm, R_(t)=14.38 min, purity=99%; column:Waters Xbridge Phenyl column 3.5 μm 4.6×150 mm, R_(t)=13.01 min,purity=99%.

2-(4-fluorophenyl)-5-(3-(3-(4-fluorophenyl)pyrrolidine-1-carbonyl)phenyl)-N-methylbenzofuran-3-carboxamide

3-(4-Fluorophenyl)pyrrolidine hydrochloride (25 mg, 0.12 mmol) was addedto a stirred suspension of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(20 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIPEA (50 μL, 0.29mmol) in DMF (0.5 mL). The reaction was stirred at r.t. overnight, thendiluted with MeOH, filtered, and purified by prep HPLC. Concentrationafforded the title compound (22 mg, 79% yield) as a pink solid. ¹H NMR(˜1:1 ratio of amide rotamers, 500 MHz, DMSO-d₆) δ ppm 8.44-8.54 (m, 1H)7.98-8.06 (m, 2H) 7.66-7.91 (m, 5H) 7.52-7.61 (m, 2H) 7.36-7.44 (m, 3H)7.33 (dd, J=8.55, 5.49 Hz, 1H) 7.18 (t, J=8.85 Hz, 1H) 7.12 (t, J=8.85Hz, 1H) 4.01 (dd, J=11.14, 7.17 Hz, 0.5H) 3.72-3.82 (m, 1.5H) 3.56-3.69(m, 1.5H) 3.36-3.55 (m, 1.5H) 2.87 (d, J=4.58 Hz, 1.5H) 2.84 (d, J=4.58Hz, 1.5H) 2.27-2.34 (m, 0.5H) 2.24 (dd, J=6.56, 3.51 Hz, 0.5H) 2.04-2.12(m, 0.5H) 2.00 (dd, J=19.84, 10.38 Hz, 0.5H). LC/MS was performed on aShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.LC/MS method: solvent A=10% CH₃CN/90% H₂O/0.1% TFA, solvent B=90%CH₃CN/10% H₂O/0.1% TFA, start % B=0, final % B=100, gradient time=3 min,stop time=4 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm;HPLC R_(t)=1.89 min, (ES+) m/z (MH⁺)=537. Analytical HPLC method:solvent A=5% CH₃CN/95% H₂O/0.1% TFA, solvent B=95% CH₃CN/5% H₂O/0.1%TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm,R_(t)=14.43 min, purity=99%; column: Waters Xbridge Phenyl 3.5 μm4.6×150 mm, R_(t)=13.18 min, purity=99%.

5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

DIEA (50 μL, 0.29 mmol) was added to a suspension of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid(50 mg, 0.13 mmol) and HATU (60 mg, 0.16 mmol) in DMF (0.5 mL). Thesolids dissolved over 5 min, at which point tert-butylamine (20 μL, 0.19mmol) was added. The solution was stirred at r.t. for 1 h, then dilutedwith CH₃CN (1 mL), filtered, purified by prep HPLC, concentrated, anddried in a vacuum oven over the weekend at 40° C. to give the titlecompound (39 mg, 69% yield) as a white powder. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 8.53 (q, J=4.37 Hz, 1H) 8.08 (s, 1H) 8.01 (dd, J=8.24, 5.80 Hz,2H) 7.92 (d, J=7.93 Hz, 2H) 7.84 (d, J=7.63 Hz, 1H) 7.77-7.82 (m, 2H)7.73-7.77 (m, 1H) 7.55 (t, J=7.63 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 2.87(d, J=4.58 Hz, 3H) 1.42 (s, 9H). ¹³C NMR (125 MHz, DMSO-d₆) δ ppm 166.20(s) 163.22 (s) 162.66 (d, J=246 Hz) 152.56 (s) 152.52 (s) 140.06 (s)136.53 (s) 135.76 (s) 129.38 (d, J=12 Hz) 129.36 (s) 128.70 (s) 127.86(s) 126.27 (s) 125.86 (s) 125.70 (d, J=2.5 Hz) 124.83 (s) 118.90 (s)115.93 (d, J=20 Hz) 113.88 (s) 111.60 (s) 50.85 (s) 28.60 (s) 26.19 (s).LC/MS method: solvent A=5% CH₃CN/95% H₂O/10 mM NH₄OAc, solvent B=95%CH₃CN/5% H₂O/10 mM NH₄OAc, start % B=0, final % B=100, gradient time=2min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm4.6×50 mm; HPLC R_(t)=1.57, (ES−) m/z (M⁻)=443. Analytical HPLC method:solvent A=5% CH₃CN/95% H₂O/0.1% TFA, solvent B=95% CH₃CN/5% H₂O/0.1%TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18min, flow rate=1 ml/min. column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm,R_(t)=11.71 min, purity=100%; column: Waters Xbridge Phenyl column 3.5μm 4.6×150 mm, R_(t)=9.53 min, purity=100%.

2-(4-Fluorophenyl)-5-hydroxy-N-methyl-6-nitrobenzofuran-3-carboxamide

To a mixture of2-(4-fluorophenyl)-5-isopropoxy-N-methyl-6-nitrobenzofuran-3-carboxamide(210.5 mg, 0.565 mmol) in CH2Cl2 (14 mL) at 0° C. under N₂ was addedtrichloroborane (1.70 mL, 1.7 mmol) (1M solution in CH₂Cl₂). The mixturewas then stirred at r.t. for 17 hr. The mixture was evaporated. Thereddish orange residue was added 7 ml H₂O, and then 3.5 ml 1N HCl, andleft standing until the solid turned yellow. The yellow solid productwas then filtered and washed with 3×3 ml H₂O and dried (182 mg, 93%). ¹HNMR (500 MHz, DMSO-d₆) δ 10.18 (broad s, 1H), 8.53 (m, 1H), 8.31 (s,1H), 7.98 (apparent dd, J=8.85, 5.49, 2H), 7.43 (apparent t, J=8.85,2H), 7.28 (s, 1H,), 2.84 (appeared as d, J=4.58, 3H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=331.21, HPLC R_(t)=1.442 min.

2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yltrifluoromethanesulfonate

To a mixture of2-(4-fluorophenyl)-5-hydroxy-N-methyl-6-nitrobenzofuran-3-carboxamide(100 mg, 0.303 mmol) in CH₂Cl₂ (4 mL) at r.t. under N₂ was addedtriethylamine (0.084 mL, 0.606 mmol). The mixture was then cooled to 0°C., and then added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(162 mg, 0.454 mmol). The orange suspension was then stirred at r.t. for23 hr. The mixture was evaporated. The grayish-green residue was added 3ml H₂O, the solid product filtered and washed with 3×3 ml H₂O and dried(130.8 mg, 89%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 1H), 8.62 (broads, 1H), 8.02 (td, J=5.65, 2.44, 2H), 7.96 (s, 1H,), 7.48 (td, J=8.77,2.59, 2H), 2.85 (appeared as d, J=3.97, 3H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18,3.0×50 mm; (ES+) m/z (M+H)⁺=463.25, HPLC R_(t)=1.700 min.

General Procedure.

A mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (or the 6-nitro analog) (0.3 mmol, 1 equiv.),3-boronobenzoic acid (1.5 equiv.), cesium carbonate (1.7 equiv.) andPd(PPh₃)₄ (0.1 equiv.) in a mixture of H₂O (0.6 mL)/1,4-dioxane (3.00mL) under N₂ was stirred at 90° C. for about 1.5 to 5 hr. The mixturewas cooled to r.t. and diluted with 3 ml 1,4-dioxane. The mixture wasfiltered through a Whatman PTFE 4.5 uM disk, and concentrated. Themixture was added 4 ml 1N HCl, diluted with 5 ml H₂O. The precipitateswere filtered and washed with 3×4 ml H2O, and dried. The crude materialwas purified as indicated or used for the amide coupling step withoutfurther purification. To a mixture of 3-(benzofuran-5-yl)benzoic acidderivative obtained from above (0.074 mmol, 1 equiv.), amine (1.5equiv.) and2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate (2 equiv.) in DMF (1 mL) at r.t. under N₂ was addedN,N-diisopropylethylamine (3 equiv.). The mixture was stirred at r.t.for about 23 hr. The mixture was diluted with MeOH and purified asindicated, e.g. by Shimadzu-VP preparative reverse phase HPLC.

4-Fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

¹H NMR (500 MHz, DMSO-d₆) δ 13.17 (s, 1H), 8.51 (q, J=4.27, 1H), 8.13(dd, J=7.78, 1.98, 1H), 8.01 (apparent dd, J=8.70, 5.34, 3H), 7.81 (d,J=8.54, 1H), 7.80 (s, 1H), 7.61 (d, J=8.54, 1H), 7.49 (dd, J=10.07,8.85, 1H), 7.41 (apparent t, J=8.85, 2H), 2.85 (appeared as d, J=4.58,3H). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=408.29, HPLCR_(t)=1.693 min.

5-(2-Fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.79-9.35 min. (UV detection at 220nm). ¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.51 (q, J=4.58, 1H),8.15 (dd, J=7.48, 2.29, 1H), 8.00 (dd, J=9.00, 5.34, 2H), 7.97 (m, 1H),7.83 (s, 1H), 7.82 (d, J=8.60, 1H), 7.64 (d, J=8.55, 1H), 7.46 (dd,J=10.22, 8.70, 1H), 7.41 (t, J=9.00, 2H), 7.29 (t, J=7.63, 1H), 7.28 (d,J=7.32, 1H,), 7.23 (apparent d, J=7.10, 2H), 7.17 (t, J=7.17, 1H), 2.85(appeared as d, J=4.58, 3H), 1.30 (appeared as d, 4H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=523.44, HPLC R_(t)=1.803 min.

5-(2-Fluoro-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.47-9.09 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD, appeared as a mixture of two isomers) δ8.06-8.04 (m, 1H), 8.00-7.97 (m, 2H), 7.90-7.87 (m, 2H), 7.70 (d,J=8.50, major) and 7.69 (d, J=8.50, minor) (1H), 7.63-7.62 (m, 1H),7.36-7.27 (overlapping m, 3H), 3.23 (d, J=7.02, major) and 3.23-3.22 (d,minor) (2H), 2.98 (s, major) and 2.97 (s, minor) (3H), 1.97 (m, 1H),1.00 (d, J=6.71, major) and 0.99 (d, J=6.71, minor) (6H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=463.38, HPLC R_(t)=1.772 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=8.85 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=6.44 min.

5-(2-Chloro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 9.28-9.85 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD, appeared as a mixture of two isomers) δ9.36 (broad s, 1H), 7.98-7.94 (overlapping m, 3H), 7.85 (dd, J=8.39,2.29, major) and 7.86-7.83 (dd, minor) (1H), 7.75 (d, J=1.83, major) and7.75-7.74 (d, minor) (1H), 7.66 (d, J=8.55, major) and 7.66-7.64 (d,minor) (1H), 7.633 (d, J=8.00, major) and 7.626 (d, J=8.50, minor) (1H),7.48 (dd, J=8.55, 1.83, major) and 7.49-7.47 (dd, minor) (1H), 7.29-7.25(overlapping m, 6H), 7.17 (m, 1H), 2.95 (s, major) and 2.94 (s, minor)(3H), 1.36-1.34 (appeared as d, 4H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=539.37, 541.38, HPLC R_(t)=1.868 min. Analytical HPLCwere performed by using Shimadzu-VP instrument with UV detection at 220nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1%TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=10.84 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=8.37 min.

5-(2-Chloro-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 9.01-9.47 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD, appeared as a mixture of two isomers) δ7.98 (major) and 7.97 (minor) (dd, 2H), 7.91 (d, J=2.14, major) and7.91-7.90 (d, minor) (1H), 7.82 (dd, J=8.24, 2.14, major) and 7.82-7.80(dd, minor) (1H), 7.75 (m, 1H), 7.65 (dd, J=16, 8.39, major) and 7.64(dd, J=16.5, 8.55, minor) (2H), 7.49 (dd, J=8.24, 1.83, major) and7.49-7.47 (dd, minor) (1H), 7.27 (t, J=8.85, major) and 7.29-7.25(apparent m, minor) (2H), 3.22 (d, J=7.02, major) and 3.21 (d, J=7.02,major) (2H), 2.96 (s, major) and 2.95 (s, minor) (3H), 1.95 (m, 1H),0.98 (d, J=6.71, major) and 0.97 (d, J=6.71, minor) (6H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=479.33, 481.36, HPLCR_(t)=1.830 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=9.66 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=7.19 min.

3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)-4-methoxybenzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=465.31, HPLCR_(t)=1.568 min.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-methoxyphenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.79-8.36 min. (UV detection at 220nm). ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (q, J=4.48, 1H), 8.48 (s, 1H),8.46 (t, J=5.80, 1H), 8.05 (dd, J=9.00, 5.34, 2H), 7.96 (dd, 1H), 7.95(apparent s, 1H), 7.68 (s, 1H), 7.46 (t, J=8.85, 2H), 7.14 (d, J=8.55,1H), 3.69 (s, 3H), 3.11 (broad d, 2H), 2.83 (appeared as d, J=4.58, 3H),1.87 (m, 1H), 0.91 (d, J=6.71, 6H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=520.40, HPLC R_(t)=1.688 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=7.93 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=6.30 min.

3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)benzoicacid

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 6.98-7.51 min. (UV detection at 220nm). ¹H NMR (500 MHz, DMSO-d₆) δ 13.17 (s, 1H), 8.60 (m, 1H), 8.54 (s,1H), 8.08-8.05 (overlapping m, 2H), 8.02 (d, J=7.63, 1H), 7.95 (s, 1H),7.74 (s, 1H), 7.67-7.61 (overlapping m, 2H), 7.46 (apprent t, J=8.85,2H), 2.84 (appeared as d, J=4.58, 3H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=435.27, HPLC R_(t)=1.588 min.

2-(4-Fluorophenyl)-N-methyl-6-nitro-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

2-(4-Fluorophenyl)-N-methyl-6-nitro-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamidewas prepared as described in the general procedure. The reaction mixturewas concentrated, and then added excess water. The off whiteprecipitates of the product were filtered, washed with 3 times of waterand dried. ¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.60 (m, 1H), 8.55(s, 1H), 8.05 (m, 2H), 7.99-7.97 (overlapping m, 2H), 7.75 (s, 1H),7.59-7.53 (overlapping m, 2H), 7.46 (t, J=8.70, 2H), 7.29 (t, J=7.02,2H), 7.24 (s, 1H), 7.23 (d, J=7.02, 1H), 7.17 (t, J=6.71, 1H,), 2.83 (s,3H), 1.29 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=550.45, HPLC R_(t)=1.738 min.

6-Amino-2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

2-(4-Fluorophenyl)-N-methyl-6-nitro-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide(83.3 mg, 0.152 mmol) under N₂ at r.t. was dissolved in DMF (2 ml) andthen added ethyl acetate (10 mL). The mixture remained as a clear lightbrown solution. The mixture was added palladium (97 mg, 0.045 mmol,5%/C), flushed with H₂ using a balloon, and the mixture stirred under H₂for about 8 hr. The mixture was diluted with EtOAc, and filtered througha Whatman PTFE 45 uM disk. The filtrate was evaporated. The residue wassaturated with 3×1 ml Et₂O (the Et₂O solution was removed by using apipette), and the light orange solid product dried (64.4 mg, 82%). ¹HNMR (500 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.32 (q, J=4.17, 1H), 7.94-7.89(overlapping m, 3H), 7.97 (s, 1H), 7.62 (d, J=6.8, 1H), 7.58 (q, 1H),7.34 (t, J=8.70, 2H), 7.29 (t, 1H), 7.28 (d, J=7.50, 1H), 7.23 (s, 2H),7.227 (d, J=8.00, 1H), 7.17 (t, J=7.17, 1H,), 6.99 (s, 1H), 5.09 (s,2H), 2.79 (appeared as d, J=3.97, 3H), 1.29 (appeared as d, 4H). LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=520.39, HPLC R_(t)=1.497 min.

2-(4-Fluorophenyl)-6-(2-methoxyacetamido)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of 2-methoxyacetic acid (10.40 mg, 0.115 mmol) in THF (3mL) at r.t. under N₂ was added 1,1′-carbonyldiimidazole (CDI) (28.1 mg,0.173 mmol). The mixture was stirred at 55° C. for 1 hr. The mixture wasthen transferred to a flask containing6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide(30 mg, 0.058 mmol) at r.t. under N₂. 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU) (0.035 mL, 0.231 mmol) was then added and the mixture was stirredat 55° C. for 2 hr 35 min. The mixture was then left standing at r.t.overnight. The mixture was re-stirred at 55° C. for 3 hr. The mixturewas cooled to r.t., diluted with MeOH and purified by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 7.28-7.84 min. (UV detection at 220 nm). ¹H NMR (500 MHz,DMSO-d₆) δ 9.29 (s, 1H), 9.04 (s, 1H), 8.49 (q, J=4.58, 1H), 8.31 (s,1H), 8.03-8.00 (overlapping m, 3H), 7.98 (m, 1H), 7.59 (s, 1H), 7.63 (s,1H), 7.625 (d, J=2.44, 1H), 7.40 (t, J=9.00, 2H), 7.28 (apparent t,J=7.63, 2H,), 7.23 (apparent d, 2H,), 7.17 (t, J=7.17, 1H,), 3.90 (s,2H), 3.18 (s, 3H), 2.83 (appeared as d, J=4.58, 3H), 1.28 (s, 4H). LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=592.49, HPLC R_(t)=1.652 min.

3-(tert-Butoxycarbonylamino)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M−Me₂CCH₂+H)⁺=449.35, HPLCR_(t)=1.808 min.

Tert-Butyl3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-(isobutylcarbamoyl)phenylcarbamate

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=70, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.13-7.93 min. (UV detection at 220nm). ¹H NMR (500 MHz, DMSO-d₆)) δ 9.57 (s, 1H), 8.55 (dt, J=10.38, 5.19,1H), 8.50 (broad s, 1H), 8.01-7.98 (m, 3H), 7.89 (s, 1H), 7.86-7.85 (m,1H), 7.81 (apparent d, 1H), 7.75 (s, 1H), 7.70 (dd, J=8.55, 1.83, 1H),7.41 (apparent t, J=8.85, 2H), 3.11 (t, J=6.41, 2H), 2.87 (appeared asd, J=4.58, 3H), 1.88 (ddd, J=13.50, 6.64, 6.41, 1H), 1.55 (s) and 1.51(s) (9H), 0.92 (d, J=6.50, major) and 0.91 (d, J=6.50, minor) (6H).LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=560.40, HPLCR_(t)=1.898 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=70, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=5.77 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=3.70 min.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)phenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.89-8.57 min. (UV detection at 220nm). ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (m, 2H), 8.54 (s, 1H), 8.05 (m,2H), 7.93 (d, J=7.63, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 7.57 (apparent t,J=7.63, 1H), 7.54 (apparent t, 1H), 7.46 (apparent t, J=8.85, 2H), 3.11(t, J=6.41, 2H), 2.84 (appeared as d, J=4.58, 3H), 1.87 (m, 1H), 0.91(d, J=6.71, 6H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=490.41,HPLC R_(t)=1.693 min. Analytical HPLC were performed by usingShimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA, SolventB=95% MeCN-5% H₂O-0.1% TFA, Start % B=70, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18,3.5 um, 4.6×150 mm, R_(t)=8.09 min; Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=6.38 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.92-9.62 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.97 (dd, J=8.85, 5.49, 2H), 7.79 (m,2H), 7.65-7.64 (d overlapping s, 1H), 7.64 (s, 1H), 7.42 (m, 1H), 7.37(dd, J=8.24, 1.83, 1H), 7.29-7.26 (overlapping m, 6H), 7.16 (m, 1H),2.95 (s, 3H), 2.34 (s, 3H), 1.36-1.33 (appeared as d, 4H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=519.40, HPLC R_(t)=1.832 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=9.93 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=7.64 min.

5-(3-Fluoro-5-(propylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.32-8.96 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 8.00-7.97 (overlapping m, 4H), 7.74-7.69(overlapping m, 2H), 7.65-7.62 (m, 1H), 7.58-7.55 (m, 1H), 7.29 (t,J=8.70, 2H), 3.39 (t, J=7.00, 2H), 3.00 (s, 3H), 1.69 (m, 2H), 1.02 (t,J=7.48, 3H). LC/MS were performed by using Shimadzu-VP instrument withUV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺ =449.40, HPLC R_(t)=1.752 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=8.08 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=5.87 min.

5-(3-(tert-Butylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.48-9.02 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.97-7.94 (overlapping m, 2H), 7.90 (dd,J=6.87, 2.59, 1H), 7.88 (s, 1H), 7.78 (ddd, J=8.47, 4.65, 2.44, 1H),7.64 (m, 2H), 7.30-7.25 (overlapping m, 3H), 2.99 (s, 3H), 1.50 (2, 9H).LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=463.36, HPLCR_(t)=1.788 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=9.97 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=6.81 min.

5-(3-Amino-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Obtained as a hydrochloride salt from the deprotection of tert-Butyl3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-(isobutylcarbamoyl)phenylcarbamateusing 4 M HCl in 1,4-dioxane (r.t.). ¹H NMR (500 MHz, CD₃OD) δ 8.26 (s,1H), 8.02 (s, 1H), 7.97 (dd, J=7.63, 5.49, 2H), 7.87 (s, 2H), 7.75 (s,2H), 7.30 (t, J=8.39, 2H), 3.28 (d, J=7.02, 2H), 2.99 (s, 3H), 2.00 (m,1H), 1.02 (d, J=6.71, 6H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=460.42, HPLC R_(t)=1.510 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=8.96 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=9.23 min.

3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.02-7.76 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 8.00-7.97 (overlapping m, 2H), 7.84 (d,J=1.53, 1H), 7.81 (dd, J=7.63, 1.83, 1H), 7.67 (d, J=8.50, 1H),7.63-7.60 (overlapping m, 2H), 7.32-7.26 (overlapping m, 3H), 3.50 (s,3H), 2.97 (s, 3H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=420.27,HPLC R_(t)=1.623 min. Analytical HPLC were performed by usingShimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA, SolventB=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18,3.5 um, 4.6×150 mm, R_(t)=6.08 min; Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=4.83 min.

2-(4-Fluorophenyl)-5-(2-methoxy-3-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.65-9.45 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.99-7.96 (overlapping m, 2H), 7.87 (d,J=1.83, 1H), 7.69-7.63 (overlapping m, 3H), 7.57 (dd, J=7.48, 1.68, 1H),7.40 (d, J=7.63, 1H), 7.39 (s, 1H), 7.34-7.27 (overlapping m, 5H), 7.20(t, J=7.17, 1H), 3.41 (s, 3H), 2.97 (s, 3H), 1.40-1.37 (appeared as d,4H). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=535.45, HPLCR_(t)=1.833 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=9.93 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=7.75 min.

5-(2-Chloro-5-(1-(2-chlorophenyl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=80, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 5.53-6.33 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.99-7.96 (overlapping m, 2H), 7.84 (d,J=2.14, 1H), 7.79 (dd, J=7.17, 1.98, 1H), 7.74 (dd, J=8.39, 2.29, 1H),7.72 (d, J=1.53, 1H), 7.65 (d, J=8.55, 1H), 7.58 (d, J=8.54, 1H), 7.45(dd, J=8.55, 1.83, 1H), 7.37 (dd, J=7.25, 1.75, 1H), 7.30-7.23(overlapping m, 4H), 2.95 (s, 3H), 1.34-1.24 (appeared as d, 4H). LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=573.38, HPLC R_(t)=1.945 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=12.00 min;Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=8.98 min.

5-(2-Chloro-5-(3-phenylpentan-3-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=80, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 6.08-6.89 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 8.00-7.97 (overlapping m, 2H), 7.87 (d,J=2.14, 1H), 7.80 (dd, J=8.24, 2.14, 1H), 7.76 (d, J=1.53, 1H), 7.68 (d,J=8.54, 1H), 7.64 (d, J=8.00, 1H), 7.50 (dd, J=8.55, 1.53, 1H), 7.42 (d,J=7.32, 2H), 7.34-7.27 (overlapping m, 4H), 7.20 (d, J=7.32, 1H), 2.96(s, 3H), 2.35 (m, 2H), 2.08 (m, 2H), 0.80 (t, J=7.32, 6H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=569.47, HPLC R_(t)=1.972 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=13.37 min;Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=10.24 min.

6-Acetamido-2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

Prepared from6-Amino-2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamidein a similar manner as described. ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (s,1H), 9.28 (s, 1H), 8.48 (m, 1H), 8.03-8.00 (overlapping m, 3H), 7.93 (m,1H), 7.89 (s, 1H), 7.58-7.56 (overlapping m, 3H), 7.40 (t, J=8.85, 2H),7.30-7.27 (overlapping m, 2H), 7.23-7.21 (overlapping m, 2H), 7.17 (t,J=7.32, 1H), 2.83 (appeared as d, J=4.58, 3H), 1.92 (s, 3H), 1.29(appeared as s, 4H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=562.42, HPLC R_(t)=1.547 min.

6-Amino-2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Obtained from the reduction of2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)phenyl)-N-methyl-6-nitrobenzofuran-3-carboxamideusing H₂ with 5% Pd/C as catalyst (1:6 DMF/EtOAc, r.t.) in a similarmanner as described. ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (t, J=5.95, 1H),8.33 (q, J=4.58, 1H), 7.94-7.91 (overlapping m, 3H), 7.85 (d, J=7.32,1H), 7.61-7.55 (overlapping m, 2H), 7.34 (t, J=8.70, 2H), 7.23 (s, 1H),6.99 (s, 1H), 5.05 (s, 2H), 3.11 (d, J=7.02, 2H), 2.80-2.79 (appeared asd, 3H), 1.87 (m, 1H), 0.91 (d, J=6.71, 6H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18,3.0×50 mm; (ES+) m/z (M+H)⁺=460.38, HPLC R_(t)=1.407 min.

5-(2-Fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.64 (s, 2H), 8.12 (dd,J=7.32, 2.14, 1H), 8.08-8.05 (overlapping m, 3H), 7.83 (s, 1H), 7.47 (t,J=8.85, 2H), 7.42 (t, J=9.30, 1H), 7.31-7.28 (overlapping m, 2H),7.25-7.23 (overlapping m, 2H), 7.17 (t, J=7.17, 1H), 2.84 (appeared asd, J=4.58, 3H), 1.31-1.28 (appeared as d, 4H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18,3.0×50 mm; (ES+) m/z (M+H)⁺=568.39, HPLC R_(t)=1.768 min. AnalyticalHPLC were performed by using Shimadzu-VP instrument with UV detection at220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95%H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=9.28 min; Column: XbridgePhenyl 3.5 um, 4.6×150 mm, R_(t)=7.82 min.

6-Amino-5-(2-fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Obtained from the reduction of5-(2-Fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamideusing H₂ with 5% Pd/C as catalyst (1:5 DMF/EtOAc, r.t.) in a similarmanner as described. LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=538.41, HPLC R_(t)=1.510 min.

6-Amino-5-(2-fluoro-5-(1-phenylpropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Obtained as a side product from the over-reduction of5-(2-Fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-nitrobenzofuran-3-carboxamideunder the conditions using H₂ with 5% Pd/C as catalyst (1:5 DMF/EtOAc,r.t.). The product was obtained as a TFA salt after purification byShimadzu-VP preparative reverse phase HPLC using the separation method:Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 6.52-7.08 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 7.98 (m, 1H), 7.93-7.91 (overlapping m, 3H), 7.51 (s, 1H),7.40-7.38 (overlapping m, 2H), 7.34 (d, J=7.60, 1H), 7.33 (t, J=7.78,2H), 7.27-7.23 (overlapping m, 4H), 4.99 (t, J=7.48, 1H), 2.92 (s, 3H),1.94 (m, 2H), 0.99 (t, J=7.32, 3H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=540.45, HPLC R_(t)=1.587 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.56 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.42 min.

5-(2-Fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

Prepared from the coupling between6-Amino-5-(2-fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideand methanesulfonyl chloride (N,N-diisopropylethylamine, C1CH₂CH₂Cl,r.t.), followed by hydrolysis of the intermediateN-(methylsulfonyl)methanesulfonamide (Cs₂CO₃, 1:5 H₂O/1,4-dioxane, 90°C.). Purification by Shimadzu-VP preparative reverse phase HPLC usingthe separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, SolventB=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradienttime=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.70-7.25 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 8.00-7.95 (overlappingm, 4H), 7.83 (s, 1H), 7.66 (s, 1H), 7.35 (t, J=9.00, 1H), 7.30-7.27(overlapping m, 6H), 7.18 (m, 1H), 2.94 (s, 3H), 2.88 (s, 3H), 1.37-1.35(appeared as d, 4H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=616.48, HPLC R_(t)=1.563 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.57 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.80 min.

5-(2-Fluoro-5-(1-phenylpropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

Prepared in a similar manner as5-(2-fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide.Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.35-7.81 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 8.00-7.93 (overlapping m, 4H), 7.83 (s,1H), 7.66 (s, 1H), 7.41 (d overlapping with s, J=8.00, 1H), 7.40 (s,1H), 7.35-7.32 (overlapping m, 3H), 7.29 (t, J=8.10, 2H), 7.25 (t,J=7.93, 1H), 4.99 (t, J=7.48, 1H), 2.94 (s, 3H), 2.89 (s, 3H), 1.94 (m,2H), 1.00 (t, J=7.17, 3H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=618.48, HPLC R_(t)=1.637 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=7.76 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=6.37 min.

Methyl2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yloxy)acetate

To a 50 mL round-bottomed flask was added2-(4-fluorophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide (285 mg, 1mmol), potassium carbonate (207 mg, 1.500 mmol), and methyl bromoacetate(0.101 ml, 1.1 mmol) in DMF (3 mL) to give a yellow suspension. Themixture was stirred at room temperature under nitrogen overnight. Thecrude product was diluted with 100 mL of dichloromethane, washed withwater, then brine and dried over magnesium sulfate. The residue waspurified using a Biotage Horizon employing a gradient of 0 to 30%methanol in dichloromethane and a 40+M silica gel column. The productwas then triturated with cold ethyl acetate to give a 73% yield (259mgs) of product, a white amorphous solid after drying under vacuum.

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B(B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grademethanol), in 2 minutes with a 1 minute hold at a rate of 5 mL/minute.The NMR spectra was recorded at room temperature using a Bruker DRX300spectrometer. Chemical shifts were reported in ppm relative to thedeuterated solvent used. Coupling constants were reported in hertz. Peakmultiplicity was reported using the following abbreviations: s(singlet), d (doublet), dd (doublet of doublets), t (triplet), m(multiplet), br (broad). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.93 (s, 3H),3.79 (s, 3H), 4.75 (s, 2H), 7.01 (dd, J=8.97, 2.38 Hz, 1H), 7.15 (d,J=2.38 Hz, 1H), 7.22 (t, J=8.78 Hz, 2H), 7.46 (d, J=8.97 Hz, 1H), 7.88(m, 2H). LCMS m/z 358.27 (M+H), Rt 1.553 min., 97.4% purity.

2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yloxy)acetic acid

To a 50 mL round-bottomed flask was added methyl2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yloxy)acetate(132.3 mg, 0.370 mmol) and 2 equivalents of potassiumtrimethylsilanolate (95 mg, 0.740 mmol) along with a 1:1 solution oftetrahydrofuran/dichloromethane (10 ml) to give a yellow heterogeneousmixture. The mixture was stirred at room temperature overnight. Thecrude product was then cooled to 0° C., diluted further withdichloromethane, and acidified with 1 N HCl. The product was extracted,washed with water then brine, and dried over magnesium sulfate. Aftersolvent evaporation, the product was triturated with hexane to give a91% yield (115 mgs), a white amorphous solid after drying under vacuum.The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B(B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grademethanol), in 2 minutes with a 1 minute hold at a rate of 5 mL/minute.The NMR spectra was recorded at room temperature using a Bruker DRX300spectrometer. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.82 (d, J=4.39 Hz, 3H),4.72 (s, 2H), 7.00 (dd, J=8.78, 2.56 Hz, 1H), 7.08 (d, J=2.56 Hz, 1H),7.35 (t, J=8.97 Hz, 2H), 7.57 (d, J=8.78 Hz, 1H), 7.92 (dd, J=8.78, 5.49Hz, 2H), 8.34 (m, 1H). LCMS m/z 344.27 (M+H), Rt 1.450 min., 96.0%purity.

2-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

To a 250 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate(3.55 g, 8.5 mmol), dioxane (50 mL), water (10 mL),Tetrakis(triphenylphosphine)palladium(0) (0.196 g, 0.170 mmol),5-borono-2-chlorobenzoic acid (2.55 g, 12.75 mmol), and cesium carbonate(4.15 g, 12.75 mmol). The tube was sealed and heated in an oil bathovernight at 85° C. The reaction mixture was then cooled, diluted with300 mL of cold 0.5M HCl and stirred for 30 minutes. The resulting solidwas washed with 0.5 N HCl then with water and allowed to dry undervacuum giving a quantitative yield of2-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid which was used without further purification. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. LCMS m/z424.77 (M+H), Rt 2.150 min., 90% purity.

3-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

To a 250 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (3.55 g, 8.5 mmol), dioxane (50 mL), water (10mL), Tetrakis(triphenylphosphine)palladium(0) (0.196 g, 0.170 mmol),5-borono-3-chlorobenzoic acid (2.55 g, 12.75 mmol), and cesium carbonate(4.15 g, 12.75 mmol). The tube was sealed and heated in an oil bathovernight at 85° C. The reaction mixture was then cooled, diluted with300 mL of cold 0.5M HCl and stirred for 30 minutes. The resulting solidwas washed with 0.5 N HCl then with water and allowed to dry undervacuum giving a quantitative yield of3-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid which was used without further purification. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. LCMS m/z424.09 (M+H), Rf 2.658 min., 88% purity.

4-Chloro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

To a 250 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate(3.55 g, 8.5 mmol), dioxane (50 mL), water (10 mL),Tetrakis(triphenylphosphine)palladium(0) (0.196 g, 0.170 mmol),3-borono-4-chlorobenzoic acid (2.55 g, 12.75 mmol), and cesium carbonate(4.15 g, 12.75 mmol). The tube was sealed and heated in an oil bathovernight at 85° C. The reaction mixture was then cooled, diluted with300 mL of cold 0.5M HCl and stirred for 30 minutes. The resulting solidwas washed with 0.5 N HCl then with water and allowed to dry undervacuum giving a quantitative yield of4-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid which was used without further purification. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 220 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (500 MHz,DMF-_(d7)) δ ppm 2.95 (d, J=4.58 Hz, 3H), 7.39-7.47 (m, 2H), 7.57 (dd,J=8.55, 1.83 Hz, 1H), 7.81 (dd, J=15.72, 8.39 Hz, 2H), 7.87 (d, J=1.83Hz, 1H), 8.04-8.14 (m, 4H), 8.40 (d, J=4.58 Hz, 1H). LCMS m/z 424.90(M+H), Rt 2.287 min. HPLC Rt 9.749 min. (Sunfire C18) and 10.518 min.(XBridge Phenyl C18), 94% purity.

5-(4-chloro-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 250 mL RBF was added2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (3.62 g, 8.55 mmol), 2-methylpropan-1-amine (1.274 mL, 12.83 mmol),N-ethyl-N,N-diisopropylamine (2.98 mL, 17.10 mmol), and 3 eq. of HATU,(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (9.75 g, 25.7 mmol)) along with 114 mL of DMF.The mixture was stirred overnight at room temperature. The crudereaction mixture was transferred to a separatory funnel, diluted with300 mL of dichloromethane and washed with 100 mL of 1 N HCl, water, andbrine. After drying over magnesium sulfate the crude residue was pushedthrough a plug of silica gel and evaporated to a tan solid. The solidwas triturated with diethyl ether then cold acetonitrile to give a 48%yield of5-(4-chloro-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,as a light yellow powder. The NMR spectrum was recorded at roomtemperature using a Bruker DRX500 spectrometer. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 220 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/0.1%ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (500 MHz,ACETONE-_(d6)) δ ppm 1.02 (d, J=6.71 Hz, 6H), 1.92-2.01 (m, 1H), 2.99(d, J=4.88 Hz, 3H), 3.28 (t, J=6.41 Hz, 2H), 7.33 (t, J=8.70 Hz, 2H),7.56 (d, J=8.24 Hz, 1H), 7.61 (br. s., 1H), 7.66 (br. s., 1H), 7.68-7.74(m, 2H), 7.74-7.82 (m, 2H), 8.01-8.06 (m, 1H), 8.13 (dd, J=8.70, 5.34Hz, 2H). LCMS m/z 479.06 (M+H), Rt 2.367 min. HPLC Rt 10.263 min.(Sunfire C18) and 11.753 min. (XBridge Phenyl C18), 93% purity.

5-(4-chloro-3-(2-phenylpropan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 2 dram vial was added2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (42.4 mg, 0.1 mmol) in DMF (2 mL) along with cumylamine (0.029 mL,0.200 mmol), N,N-Diisopropylethylamine (0.035 mL, 0.200 mmol) and HATU(114 mg, 0.300 mmol) to give a yellow solution. The vial was shaken atroom temperature overnight. The crude reaction mixture was thenevacuated to near dryness, taken up in 2 mL of methanol and purifiedusing a Shimadzu preparative HPLC employing methanol/water/0.1% TFAwhere solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid andsolvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid with aPhenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 30-100% Band a flow rate of 40 mL/min. over 10 minutes with a 10 minute hold. Thetubes containing purified product were evaporated overnight in aSavant/Thermo Speedvac to give a 45% yield of5-(4-chloro-3-(2-phenylpropan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a white powder. The NMR spectrum was recorded at room temperatureusing a Bruker DRX300 spectrometer. The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column,with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 3 minutes with a 1minute hold at a rate of 4 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 220 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.87 (s, 6H), 3.02 (d,J=4.76 Hz, 3H), 6.03 (d, J=4.76 Hz, 1H), 6.62 (s, 1H), 7.13-7.23 (m,2H), 7.24-7.31 (m, 1H), 7.33-7.42 (m, 2H), 7.45 (d, J=8.42 Hz, 1H),7.48-7.63 (m, 5H), 7.83-8.00 (m, 4H).

LCMS m/z 542.90 (M+H), Rt 2.608 min. HPLC Rt 11.069 min. (Sunfire C18)and 12.111 min. (XBridge Phenyl C18), 97.8% purity.

2-(4-fluorophenyl)-N-methyl-5-(2-(2-phenylpropan-2-ylcarbamoyl)biphenyl-4-yl)benzofuran-3-carboxamide

To a 2 mL microwave vial was added dioxane (2 mL), water (0.200 mL),(S-Phos) dicyclohexyl (2′,6′-dimethoxybiphenyl-2-yl)phosphine, (1.912mg, 4.66 μmol),5-(4-chloro-3-(2-phenylpropan-2-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.0126 g, 0.023 mmol), potassium phosphate tribasic (0.020 g, 0.093mmol), palladium(II) acetate (1.046 mg, 4.66 μmol), and phenylboronicacid (8.52 mg, 0.070 mmol). The vial was capped, degassed, flushed withN₂ and heated in the microwave for 10 minutes at 150° C. The crudeproduct was taken up in a 1:1 solution of DMF/acetonitrile and purifiedby a Shimadzu preparative HPLC employing acetonitrile/0.1% TFA/waterwhere solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acidand solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acidwith a Waters-Atlantis OBD 19×100 mm 5 μm column at a gradient of50-100% B and a flow rate of 25 mL/min. over 10 minutes with a 10 minutehold. The purified product was evaporated to dryness overnight in aSavant Thermo Speedvac to give a 73% yield of2-(4-fluorophenyl)-N-methyl-5-(2-(2-phenylpropan-2-ylcarbamoyl)biphenyl-4-yl)benzofuran-3-carboxamide.The NMR spectrum was recorded at room temperature using a Bruker DRX500spectrometer. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of4 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 220 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (500 MHz,CD₃OD) δ ppm 1.54 (s, 6H), 3.01 (s, 3H), 7.15-7.20 (m, 1H), 7.21-7.33(m, 6H), 7.43-7.50 (m, 3H), 7.51-7.55 (m, 3H), 7.69-7.72 (m, 1H),7.72-7.76 (m, 1H), 7.80 (d, J=1.53 Hz, 1H), 7.84 (dd, J=7.93, 1.83 Hz,1H), 7.96-8.02 (m, 3H), 8.10 (br. s., 1H). LCMS m/z 583.03 (M+H), Rt2.811 min. HPLC Rt 11.683 min. (Sunfire C18) and 12.609 min. (XBridgePhenyl C18), 99% purity.

5-(3-chloro-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 250 mL round-bottomed flask was added3-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (3.62 g, 8.55 mmol), 2-methylpropan-1-amine (1.274 mL, 12.83 mmol),N-ethyl-N,N-diisopropylamine (2.98 mL, 17.10 mmol), and 3 eq. of HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluoro-phosphate(V) (9.75 g, 25.7 mmol)) along with 114 mL of DMF.The mixture was stirred overnight at room temperature. The crudereaction mixture was transferred to a separatory funnel, diluted with300 mL of dichloromethane and washed with 100 mL of 1 N HCl, water, andbrine. After drying over magnesium sulfate the crude residue was pushedthrough a plug of silica gel and evaporated to a tan solid. The solidwas triturated with diethyl ether then cold acetonitrile to give a 52%yield of5-(4-chloro-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,as a light yellow powder. The NMR spectrum was recorded at roomtemperature using a Bruker DRX500 spectrometer. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 220 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 0.94 (d, J=6.41 Hz, 6H), 1.72-1.97 (m, 1H), 2.87 (d,J=4.58 Hz, 3H), 3.10 (t, J=6.26 Hz, 2H), 7.40 (t, J=8.85 Hz, 2H), 7.59(d, J=8.55 Hz, 1H), 7.69-7.75 (m, 2H), 7.76-7.82 (m, 2H), 7.90 (br. s.,1H), 7.97-8.07 (m, 2H), 8.55 (br. s., 2H). LCMS m/z 479.04 (M+H), Rt2.658 min. HPLC Rt 10.810 min. (Sunfire C18) and 12.154 min. (XBridgePhenyl C18), 92% purity.

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoicacid

To a 150 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate(1.252 g, 3 mmol), 3-borono-4-methoxybenzoic acid (0.882 g, 4.50 mmol),cesium carbonate (1.466 g, 4.50 mmol), tetrakis(triphenylphosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane (18 mL) and water(3.60 mL). The vial was sealed and heated in an oil bath over night at85° C. The reaction mixture was then filtered through celite andconcentrated in vacuo. Cold 0.5N HCl was then added and theheterogeneous mixture was stirred for 30 minutes. The resulting product,a white solid was filtered, washed with water and dried overnight togive a quantitative yield of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoic acid which was carried on without further purification. LCMS m/z420.88 (M+H), Rt 2.002 min., 88% purity.

5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid

To a 150 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (1.252 g, 3 mmol), 5-borono-2-methoxybenzoicacid (0.882 g, 4.50 mmol), cesium carbonate (1.466 g, 4.50 mmol),tetrakis(triphenyl phosphine)palladium(0) (0.069 g, 0.060 mmol), dioxane(18 mL) and water (3.60 mL). The vial was sealed and heated in an oilbath over night at 85° C. The reaction mixture was then filtered throughcelite and concentrated in vacuo. Cold 0.5N HCl was then added and theheterogeneous mixture was stirred for 30 minutes. The resulting product,a white solid was filtered, washed with water and dried overnight togive a quantitative yield of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoic acid which was carried on without further purification. LCMS m/z420.92 (M+H), Rt 2.003 min., 87% purity.

2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-methoxyphenyl)-N-methylbenzo-furan-3-carboxamide

To a vial containing(5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid (378.5 mg, 0.902 mmol)) was added DMF (5 mL),N,-ethyl-N,N-diisopropylamine (0.786 mL, 4.51 mmol),2-methylpropan-1-amine (0.448 mL, 4.51 mmol), and HATU,(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1029 mg, 2.71 mmol)). The vial was capped andthe solution shaken overnight at room temperature. The crude product wasdiluted with ethyl acetate, washed with 0.5M HCl, and extracted. Theorganic layer was washed with brine, dried over magnesium sulfate,filtered and concentrated. The crude reaction mixture was taken up inacetonitrile, filtered and purified using a Shimadzu preparative HPLCemploying acetonitrile/water/TFA where solvent A was 10%acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10%H2O/90% acetonitrile/0.1% trifluoroacetic acid with a Phenomenex-Luna 10μm C18 30×100 mm at a gradient of 40-100% B and a flow rate of 25mL/min. over 10 minutes with a 10 minute hold. The purified product wasconcentrated in vacuo to give a 38% yield of2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-methoxyphenyl)-N-methylbenzo-furan-3-carboxamideas a white solid. The NMR spectrum was recorded at room temperatureusing a Bruker DRX500 spectrometer. The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column,with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 3 minutes with a 1minute hold at a rate of 4 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 220 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (500 MHz, Acetone-_(d6)) δ ppm 1.00 (d, J=6.41 Hz,6H), 1.92-1.96 (m, 1H), 3.01 (d, J=4.27 Hz, 3H), 3.30 (t, J=6.26 Hz,2H), 4.09 (s, 3H), 7.23-7.39 (m, 3H), 7.61 (br. s., 1H), 7.69 (s, 2H),7.84 (dd, J=8.39, 1.98 Hz, 1H), 7.99 (s, 1H), 8.13 (dd, J=7.93, 5.49 Hz,3H), 8.39 (d, J=2.14 Hz, 1H). LCMS m/z 475.15 (M+H), Rt 2.452 min. HPLCRt 10.648 min. (Sunfire C18) and 12.301 min. (XBridge Phenyl C18), 100%purity.

2-(4-fluorophenyl)-5-(4-methoxy-3-(2-phenylpropan-2-ylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a vial containing(5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid (61 mg, 0.145 mmol)) was added DMF (2 mL),N,-ethyl-N,N-diisopropylamine (0.050 mL, 0.29 mmol), cumylamine (39.3mg, 0.291 mmol), and finally TBTU,o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (140mg, 0.436 mmol)). The vial was capped and the solution shaken overnightat room temperature. The crude product was diluted with ethyl acetate,washed with 1M HCl, and extracted. The organic layer was washed withbrine, dried over magnesium sulfate, filtered and concentrated. Thecrude reaction mixture was taken up in acetonitrile, filtered andpurified using a Shimadzu preparative HPLC employingacetonitrile/water/TFA where solvent A was 10% acetonitrile/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1%trifluoroacetic acid with a Phenomenex-Luna 10 μm C18 30×100 mm at agradient of 40-100% B and a flow rate of 25 mL/min. over 10 minutes witha 10 minute hold. The purified product was concentrated in vacuo to givea 42% yield of2-(4-fluorophenyl)-5-(4-methoxy-3-(2-phenylpropan-2-ylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideas a white solid. The NMR spectrum was recorded at room temperatureusing a Bruker DRX500 spectrometer. The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column,with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 3 minutes with a 1minute hold at a rate of 4 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 220 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (500 MHz, CD3OD) δ ppm 1.69-1.88 (m, 6H), 2.99 (s,3H), 4.09 (s, 3H), 7.20-7.32 (m, 4H), 7.36 (t, J=7.63 Hz, 2H), 7.52 (d,J=8.24 Hz, 2H), 7.57-7.64 (m, 2H), 7.79-7.89 (m, 2H), 7.96 (t, J=6.10Hz, 2H), 8.12 (br. s., 1H). LCMS m/z 537.13 (M+H), Rt 2.705 min. HPLC Rt11.563 min. (Sunfire C18) and 12.876 min. (XBridge Phenyl C18), 93%purity.

2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-methoxyphenyl)-N-methylbenzofuran-3-carboxamide

To a 100 mL round-bottomed flask was added3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoicacid (1258 mg, 3 mmol), DMF (40 mL), 2-methylpropan-1-amine (447 μL,4.50 mmol), N-ethyl-N,N-diisopropylamine (1.1 mL, 6.00 mmol), andfinally HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (3422 mg, 9.00 mmol)). The mixture was stirredover night at room temperature. The crude product was diluted with ethylacetate, washed with 1M HCl, and extracted. The organic layer was washedwith brine, dried over magnesium sulfate, filtered and concentrated. Thecrude residue was loaded onto 40M Biotage column and purified using aBiotage Horizon with 2200 mL of 0-6% methanol in DCM). The product wasconcentrated in vacuo then triturated with cold acetonitrile to give a60% yield of2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-methoxyphenyl)-N-methylbenzofuran-3-carboxamide as a light yellow solid. The NMR spectrum wasrecorded at room temperature using a Bruker DRX500 spectrometer. TheLC/MS data was obtained on a Shimadzu analytical LC/Micromass PlatformLC (ESI+) at 220 nm using the following set of conditions: WatersSunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90%HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water),(A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 3 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at220 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (500 MHz,CD₃OD) δ ppm 0.89-1.07 (m, 6H), 1.96 (dt, J=13.43, 6.71 Hz, 1H), 2.97(s, 3H), 3.22 (d, J=6.10 Hz, 2H), 3.80-3.98 (m, 3H), 7.19 (d, J=9.46 Hz,1H), 7.24-7.33 (m, 2H), 7.52-7.57 (m, 1H), 7.57-7.65 (m, 1H), 7.80 (s,1H), 7.84-7.92 (m, 2H), 7.96-8.02 (m, 2H), 8.46 (br. s., 1H). LCMS m/z475.02 (M+H), Rt 2.290 min. HPLC Rt 14.374 min. (Sunfire C18) and 15.689min. (XBridge Phenyl C18), 95% purity.

2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzo-furan-3-carboxamide

To a 250 mL sealed tube was added toluene (150 mL)2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-methoxyphenyl)-N-methylbenzofuran-3-carboxamide(1.187 g, 2.50 mmol) and finally, under a steady stream of N₂ Borontribromide-methyl sulfide complex (8.76 g, 28.0 mmol) was quickly added.The tube was sealed and heated to 100° C. in an oil bath for 30 hours.The crude reaction mixture was cooled to room temperature, filtered,washed with wet hexane, then diethyl ether and dried overnight undervacuum to give a 96% yield of a tan solid. The NMR spectrum was recordedat room temperature using a Bruker DRX500 spectrometer. The LC/MS datawas obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at220 nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 220 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (500 MHz,DMF-d₇) δ ppm 0.92 (d, J=6.71 Hz, 6H), 1.86-1.97 (m, 1H), 2.94-2.98 (m,3H), 3.17-3.23 (m, 2H), 7.19 (d, J=8.55 Hz, 1H), 7.42 (t, J=9.00 Hz,2H), 7.66-7.75 (m, 2 H), 7.88 (dd, J=8.39, 2.29 Hz, 1H), 8.06-8.14 (m,3H), 8.37-8.46 (m, 2H). LCMS m/z 461.95 (M+H), Rt 2.033 min. HPLC Rt8.929 min. (Sunfire C18) and 11.454 min. (XBridge Phenyl C18), 96%purity.

General Procedure.

To a 2 dram vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(46.0 mg, 0.1 mmol), DMF (2 mL), and 1.5 equivalents (0.15 mmol) ofeither triethyl amine or potassium carbonate and 1.5 equivalents (0.15mmol) of alkyl bromide. The vials were sealed and shaken at 22-70° C. ina dry bath. Upon reaction completion the crude products wereconcentrated, diluted with 2 mL of acetonitrile and purified using aShimadzu preparative HPLC employing acetonitrile/water/0.1% TFA wheresolvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid andsolvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid with aWaters Sunfire 5 μm C18 4.6×100 mm column at a gradient of 30-100% B anda flow rate of 40 mL/min. over 8 minutes with a 10 minute hold. Thedesired products were evaporated to dryness in a Savant Speedvacovernight obtaining 25-60% yield of the desired ethers as white powders.

2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-isopropoxyphenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 1.00 (d, J=6.71 Hz, 6H), 1.32 (d, J=6.10Hz, 6H), 1.87-2.05 (m, 1H), 2.98 (s, 3H), 3.22 (d, J=7.02 Hz, 2H),4.64-4.79 (m, 1H), 7.18 (d, J=8.55 Hz, 1H), 7.24-7.36 (m, 2H), 7.57-7.67(m, 2H), 7.85 (dd, J=8.55, 2.44 Hz, 1H), 7.87 (s, 1H), 7.90 (d, J=2.44Hz, 1H), 7.95-8.01 (m, 2H). LCMS m/z 503.12 (M+H), Rt 2.368 min. HPLC Rt10.789 min. (Sunfire C18) and 12.428 min. (XBridge Phenyl C18), 98.7%purity.

5-(2-(cyclobutyloxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 0.99 (d, J=6.41 Hz, 6H), 1.71-1.81 (m,1H), 1.83-1.91 (m, 1H), 1.92-2.00 (m, 1H), 2.08-2.20 (m, 2H), 2.45-2.56(m, 2H), 2.99 (s, 3H), 3.22 (d, J=6.71 Hz, 2H), 4.80-4.84 (m, 1H), 7.01(d, J=8.55 Hz, 1H), 7.28 (t, J=8.55 Hz, 2H), 7.58-7.66 (m, 2H), 7.83 (d,J=8.24 Hz, 1H), 7.86-7.92 (m, 2H), 7.96-8.03 (m, 2H). LCMS m/z 515.21(M+H), Rt 2.613 min. HPLC Rt 11.161 min. (Sunfire C18) and 12.693 min.(XBridge Phenyl C18), 97% purity.

5-(2-(cyclopentyloxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.78 Hz, 6H), 1.63-1.82 (m,4H), 1.83-2.08 (m, 5H), 3.02 (s, 3H), 3.27 (d, J=7.03 Hz, 2H), 5.02(ddd, J=5.21, 2.89, 2.70 Hz, 1H), 7.21 (d, J=8.78 Hz, 1H), 7.28-7.36 (m,2H), 7.58-7.69 (m, 2H), 7.88 (dd, J=8.53, 2.51 Hz, 1H), 7.91 (d, J=1.25Hz, 1H), 7.95 (d, J=2.26 Hz, 1H), 7.99-8.06 (m, 2H). LCMS m/z 529.16(M+H), Rt 2.685 min. HPLC Rt 12.879 min. (XBridge Phenyl C18), 100%purity.

2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-propoxyphenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (m, 9H), 1.75-1.90 (m, 2H), 1.93-2.10(m, 1H), 3.02 (s, 3H), 3.27 (d, J=7.03 Hz, 2H), 4.11 (t, J=6.15 Hz, 2H),7.21 (d, J=8.53 Hz, 1H), 7.32 (t, J=8.78 Hz, 2H), 7.59-7.72 (m, 2H),7.88-7.98 (m, 3H), 7.98-8.08 (m, 2H). LCMS m/z 503.14 (M+H), Rt 2.548min. HPLC Rt 12.554 min. (XBridge Phenyl C18), 100% purity.

2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(isopentyloxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 0.93-1.01 (m, 6H), 1.04 (d, J=6.78 Hz,6H), 1.69 (q, J=6.53 Hz, 2H), 1.83 (ddd, J=13.61, 6.71, 6.53 Hz, 1H),2.01 (dt, J=13.74, 6.81 Hz, 1H), 3.03 (s, 3H), 3.27 (d, J=7.03 Hz, 2H),4.18 (t, J=6.27 Hz, 2H), 7.22 (d, J=8.78 Hz, 1H), 7.28-7.39 (m, 2H),7.56-7.72 (m, 2H), 7.86-7.98 (m, 3H), 7.99-8.09 (m, 2H). LCMS m/z 531.16(M+H), Rt 2.791 min. HPLC Rt 13.122 min. (XBridge Phenyl C18), 100%purity.

2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-ethoxyphenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.53 Hz, 6H), 1.42 (t, J=6.78Hz, 3H), 1.90-2.11 (m, 1H), 3.02 (s, 3H), 3.27 (d, J=7.03 Hz, 2H), 4.22(q, J=6.78 Hz, 2H), 7.18-7.24 (m, 1H), 7.29-7.38 (m, 2H), 7.64-7.67 (m,2H), 7.87-7.93 (m, 2H), 7.93-7.96 (m, 1H), 8.00-8.08 (m, 2H). LCMS m/z489.15 (M+H), Rt 2.432 min. HPLC Rt 10.571 min. (Sunfire C18) and 12.193min. (XBridge Phenyl C18), 93% purity.

2-(4-fluorophenyl)-5-(2-methoxy-5-(2-phenylpropan-2-ylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a 50 mL RBF was added3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoicacid (433.9 mg, 1.035 mmol), DMF (15 mL), 2-phenylpropan-2-amine (210mg, 1.552 mmol), N-ethyl-N-isopropylpropan-2-amine (0.360 mL, 2.069mmol), and finally HATU,2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1180 mg, 3.10 mmol)). The mixture was stirredover night at room temperature. The resulting mixture was diluted withdichloromethane, washed with 0.5M HCl, then brine and dried over MgSO₄.The solution was concentrated to give a tan oil. The crude product wastaken up in 10 mL of acetonitrile and purified using a Shimadzupreparative HPLC employing acetonitrile/water/0.1% TFA where solvent Awas 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was10% H2O/90% acetonitrile/0.1% trifluoroacetic acid with aPhenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 40-100% Band a flow rate of 40 mL/min. over 8 minutes with a 12 minute hold togive a 80% yield of product as a white powder. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 220 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. All NMR spectrawere recorded at room temperature using a Bruker DRX400 spectrometer.LCMS m/z 537.18 (M+H), Rt 2.492 min. HPLC Rt 10.694 min. (Sunfire C18),99.6% purity and 12.230 min. (XBridge Phenyl C18), 99.6% purity. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.82 (s, 6H), 3.01 (s, 3H), 3.94 (s, 3H),7.18-7.27 (m, 2H), 7.28-7.40 (m, 4 H), 7.50 (d, J=7.53 Hz, 2H),7.57-7.67 (m, 2H), 7.85 (d, J=1.00 Hz, 1H), 7.89-7.95 (m, 2H), 7.98-8.09(m, 2H).

2-(4-fluorophenyl)-5-(2-methoxy-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a 50 mL RBF was added3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoicacid (433.9 mg, 1.035 mmol), DMF (15 mL), 1-phenylcyclopropanamine, HCl(214 mg, 1.259 mmol), N-ethyl-N-isopropylpropan-2-amine (0.438 mL, 2.52mmol), and finally HATU,2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1180 mg, 3.10 mmol)). The mixture was stirredover night at room temperature. The reaction mixture was diluted withdichloromethane, washed with 0.5M HCl, then brine and dried over MgSO₄.The solution was concentrated to give a tan oil. The crude product wastaken up in 10 mL of acetonitrile and purified using a Shimadzupreparative HPLC employing acetonitrile/water/0.1% TFA where solvent Awas 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was10% H2O/90% acetonitrile/0.1% trifluoroacetic acid with aPhenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 40-100% Band a flow rate of 40 mL/min. over 8 minutes with a 12 minute hold togive a 77% yield of product as a white powder. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 220 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. All NMR spectrawere recorded at room temperature using a Bruker DRX400 spectrometer.LCMS m/z 535.16 (M+H), Rt 2.373 min. HPLC Rt 10.314 min. (Sunfire C18),95.78% purity and 12.230 min. (XBridge Phenyl C18), 99.6% purity. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.40 (dd, J=7.03, 2.01 Hz, 4H), 3.01 (s, 3H),3.94 (s, 3H), 7.18-7.26 (m, 2 H), 7.28-7.38 (m, 6H), 7.56-7.62 (m, 1H),7.62-7.67 (m, 1H), 7.85 (d, J=1.51 Hz, 1H), 7.94-8.05 (m, 4H).

General Procedure.

To a Biotage microwave vial (2-5 mL) was added5-(4-chloro-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.075 mmol, 1 eq.) in dry 1,4-Dioxane (1 mL) along with the desiredboronic acid (0.150 mmol, 2 eq.), potassium phosphate, tribasic (0.300mmol, 52.3 mg) in water (0.2 mL),dicyclohexyl(2′,6′-dimethoxybiphenyl-3-yl)phosphine (S-Phos) (6.16 mg,0.015 mmol), and finally palladium (II) acetate (3.37 mg, 0.015 mmol) in1,4-dioxane (0.5 mL). The vial was flushed with nitrogen then capped andplaced into a Biotage microwave for 10 minutes at 150° C. The solventwas removed in a Thermo/Savant SpeedVac and the crude products weredissolved in DMF (1.8 mL) and purified by preparative HPLC employing aDionex PrepHPLC system equipped with an ELS (Evaporative LightScattering) detector. A Phenomenex Gemini 5 μm C18 21.2×250 mm columnwas used with acetonitrile/HPLC grade water/20 mM ammonium acetate wheresolvent A was HPLC grade water with 20 mM ammonium acetate and solvent Bwas 100% acetonitrile at a gradient of 30-95% B in 23.5 minutes with a2.5 minute hold at 20 mL/minute.

HPLC purity was determined using a Waters ZQ with ESCi mass spectrometerwith a Supelco Ascentis 2.7 μm C18 4.6×50 mm column employingacetonitrile/HPLC grade water/0.1% trifluoroacetic acid where solvent Awas 5% acetonitrile, 95% HPLC grade water with 0.1% trifluoroacetic acidand solvent B was 95% acetonitrile, 5% HPLC grade water with 0.1%trifluoroacetic acid at a gradient of 10-95% B in 8 minutes with a 1minute hold at 2 mL/minute. The NMR spectra were recorded at roomtemperature using a Varian 400 MHz flow spectrometer. Chemical shiftswere reported in ppm relative to the DMSO-d6/CDCl₃ solvent used.

2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(pyridin-3-yl)phenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 522.19 (M+H), Rt 3.21 min., 100% purity.

2-(4-fluorophenyl)-5-(3′-(hydroxymethyl)-2-(isobutylcarbamoyl)biphenyl-4-yl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.76 (d, J=6.74 Hz, 6H), 1.68 (m, 1H), 2.29 (s, 3H),2.81-3.00 (m, 4H), 7.07-7.18 (m, 1H), 7.22 (t, J=7.47 Hz, 1H), 7.26-7.37(m, 2H), 7.39 (s, 1H), 7.48 (d, J=7.91 Hz, 1H), 7.72 (br. s., 2H), 7.80(d, J=8.20 Hz, 1H), 7.92 (s, 1H), 8.01 (dd, J=7.47, 5.42 Hz, 2H), 8.22(s, 2H), 8.46 (br. s., 1H). LCMS m/z 551.23 (M+H), Rt 4.23 min., 100%purity.

5-(3′-ethoxy-2-(isobutylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 565.24 (M+H), Rt 5.28 min., 93.4% purity.

2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.93 (d, J=6.74 Hz, 6H), 1.82-1.99 (m, 1H), 2.37 (s, 3H),2.89-3.00 (m, 2H), 3.94 (s, 3H), 7.15-7.25 (m, 1H), 7.25-7.33 (m, 1H),7.39 (t, J=8.20 Hz, 1H), 7.62-7.82 (m, 5 H), 7.93 (d, J=12.89 Hz, 1H),8.02-8.12 (m, 1H), 8.36-8.45 (m, 1H), 8.53 (d, 1H).

LCMS m/z 525.21 (M+H), Rt 4.00 min., 100% purity.

2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(isoquinolin-4-yl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.64 (d, J=6.44 Hz, 6H), 1.38-1.48 (m, 1H), 2.37 (s, 3H),2.93-3.02 (m, 2H), 7.14-7.24 (m, 2H), 7.25-7.33 (m, 2H), 7.40 (t, J=8.79Hz, 1H), 7.57 (d, J=7.32 Hz, 1H), 7.75 (br. s., 2H), 7.81-7.90 (m, 1H),7.95-8.03 (m, 2H), 8.08 (br. s., 2H), 8.18-8.25 (m, 1H), 8.31-8.37 (m,1H), 8.48 (s, 1H), 8.55 (br. s., 1H). LCMS m/z 572.22 (M+H), Rt 3.49min., 100% purity.

2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(2-methoxypyridin-3-yl)phenyl)-N-methylbenzo-furan-3-carboxamide

¹H NMR δ ppm 0.88 (d, J=6.74 Hz, 6H), 1.68-1.83 (m, 1H), 2.37 (s, 3H),2.96 (d, J=4.69 Hz, 2H), 3.86 (s, 3H), 7.04-7.13 (m, 1H), 7.21 (d,J=7.32 Hz, 1H), 7.28 (d, J=7.03 Hz, 1H), 7.39 (t, J=8.05 Hz, 1H), 7.48(d, J=8.49 Hz, 1H), 7.67 (d, J=7.03 Hz, 1H), 7.82 (s, 2H), 7.88 (br. s.,2H), 8.04 (s, 1H), 8.06-8.12 (m, 1H), 8.18 (d, J=4.98 Hz, 1H), 8.54 (br.s., 1H). LCMS m/z 552.21 (M+H), Rt 4.56 min., 90.5% purity.

2-(4-fluorophenyl)-5-(2-(isobutylcarbamoyl)-4′-isopentylbiphenyl-4-yl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.99 (dd, J=12.74, 6.59 Hz, 9 H), 1.23-1.37 (m, 3H),1.59-1.70 (m, 1H), 1.88-2.00 (m, 1H), 2.37 (s, 3H), 2.76-2.87 (m, 2H),2.91-2.99 (m, 2H), 3.10-3.20 (m, 2H), 7.14-7.25 (m, 1H), 7.29 (t, J=7.32Hz, 1H), 7.38 (t, J=8.05 Hz, 2H), 7.64 (s, 1H), 7.72 (dd, J=16.26, 8.05Hz, 2H), 7.93 (s, 1H), 8.01-8.11 (m, 2H), 8.44 (br. s., 1H), 8.52 (br.s., 1H). LCMS m/z 515.26 (M+H), Rt 5.63 min., 100% purity.

2-(4-fluorophenyl)-5-(2-(isobutylcarbamoyl)-2′-methoxybiphenyl-4-yl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.85 (d, J=6.74 Hz, 6H), 1.63-1.77 (m, 1H), 2.37 (s, 3H),2.96 (d, J=4.39 Hz, 2H), 3.77 (s, 3H), 6.99-7.09 (m, 1H), 7.21 (d,J=7.62 Hz, 1H), 7.29 (t, J=7.62 Hz, 2H), 7.34-7.46 (m, 3 H), 7.76-7.88(m, 3H), 7.92-7.98 (m, 1H), 8.02 (s, 1H), 8.09 (dd, J=7.76, 6.00 Hz,2H), 8.54 (br. s., 1H). LCMS m/z 551.22 (M+H), Rt 5.07 min., 93.7%purity.

(E)-3-(4′-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2′-(isobutylcarbamoyl)biphenyl-3-yl)acrylicacid

¹H NMR δ ppm 0.81 (d, J=6.44 Hz, 6H), 1.65-1.77 (m, 1H), 2.37 (s, 3H),2.96 (d, J=4.39 Hz, 2H), 6.55 (d, J=15.82 Hz, 1H), 7.14-7.25 (m, 2H),7.25-7.33 (m, 1H), 7.40 (t, J=8.49 Hz, 2H), 7.47-7.56 (m, 1H), 7.61 (d,J=8.20 Hz, 1H), 7.67 (br. s., 1H), 7.73 (br. s., 1H), 7.80 (br. s., 2H),7.90 (d, J=7.91 Hz, 1H), 8.01 (s, 1H), 8.04-8.13 (m, 1H), 8.36 (br. s.,1H), 8.53 (br. s., 1H). LCMS m/z 591.23 (M+H), Rt 4.37 min., 100%purity.

4′-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2′-(isobutylcarbamoyl)biphenyl-3-carboxylicacid

¹H NMR δ ppm 0.80 (d, J=6.74 Hz, 6H), 1.67-1.79 (m, 1H), 2.37 (s, 3H),2.96 (d, J=4.69 Hz, 2H), 7.16-7.25 (m, 2H), 7.26-7.32 (m, 1H), 7.33-7.44(m, 2H), 7.50-7.62 (m, 2H), 7.66-7.73 (m, 1H), 7.76-7.84 (m, 2H), 7.90(d, J=7.91 Hz, 1H), 7.95-8.02 (m, 1H), 8.04-8.14 (m, 2H), 8.32-8.37 (m,1H), 8.55 (br. s., 1H). LCMS m/z 565.22 (M+H), Rt 4.22 min., 100%purity.

5-(4-(1H-indol-6-yl)-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 560.23 (M+H), Rt 4.90 min., 97.2% purity.

2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(1-propyl-1H-pyrazol-4-yl)phenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 553.25 (M+H), Rt 4.49 min., 96% purity.

5-(2′-chloro-2-(isobutylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.85 (d, J=6.44 Hz, 6H), 1.65-1.80 (m, 1H), 2.37 (s, 3H),2.93-2.97 (m, 2H), 7.06 (br. s., 1H), 7.15-7.24 (m, 2H), 7.25-7.35 (m,2H), 7.35-7.47 (m, 4H), 7.49-7.55 (m, 1H), 7.79-7.86 (m, 1H), 7.87-7.93(m, 1H), 7.98-8.13 (m, 2H), 8.21-8.27 (m, 1H), 8.53 (br. s., 1H). LCMSm/z 556.19 (M+H), Rt 5.28 min., 100% purity.

4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-N2-isobutylbiphenyl-2,2′-dicarboxamide

¹H NMR δ ppm 0.69 (d, J=6.44 Hz, 6H), 1.42-1.54 (m, 1H), 2.37 (s, 3H),2.92-2.97 (m, 2H), 7.13-7.23 (m, 2H), 7.23-7.33 (m, 2H), 7.39 (t, J=8.64Hz, 1H), 7.43-7.51 (m, 2H), 7.61 (d, J=4.69 Hz, 1H), 7.75-7.82 (m, 2H),7.86 (s, 1H), 7.96-8.03 (m, 1H), 8.08 (d, J=5.27 Hz, 1H), 8.13-8.18 (m,1H), 8.51 (br. s., 1H), 8.65 (br. s., 1H). LCMS m/z 564.24 (M+H), Rt4.07 min., 98.9% purity.

5-(2′-acetamido-2-(isobutylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.50-0.73 (m, 6H), 1.33-1.50 (m, 1H), 1.90 (s, 3H), 2.37(s, 3H), 2.92-2.97 (m, 2H), 7.20 (t, J=7.91 Hz, 3H), 7.25-7.44 (m, 6H),7.75-7.82 (m, 2H), 7.91 (s, 1H), 7.96-8.03 (m, 1H), 8.04-8.11 (m, 1H),8.24 (br. s., 1H), 8.52 (br. s., 1H, 9.89-9.96 (m, 1H). LCMS m/z 578.24(M+H), Rt 4.26 min., 93.5% purity.

2-(4-fluorophenyl)-5-(2′-(hydroxymethyl)-2-(isobutylcarbamoyl)biphenyl-4-yl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.71 (d, J=5.27 Hz, 6H), 1.45-1.57 (m, 1H), 2.37 (s, 3H),2.90 (br. s., 2H), 2.96 (d, J=4.69 Hz, 2H), 7.13-7.25 (m, 2H), 7.25-7.35(m, 1H), 7.35-7.44 (m, 3H), 7.56 (d, J=7.32 Hz, 1H), 7.81 (s, 2H),7.83-7.89 (m, 2H), 8.01 (s, 1H), 8.09 (dd, J=8.64, 5.42 Hz, 2H), 8.52(br. s., 1H). LCMS m/z 551.22 (M+H), Rt 4.58 min., 96% purity.

2-(4-fluorophenyl)-5-(2-(isobutylcarbamoyl)-2′-(methoxymethyl)biphenyl-4-yl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.64-0.79 (m, 6H), 1.47-1.59 (m, 1H), 2.37 (s, 3H),2.86-2.93 (m, 2H), 2.93-2.99 (m, 2H), 3.25 (s, 3H), 7.15-7.25 (m, 2H),7.26-7.32 (m, 1H), 7.33-7.44 (m, 4H), 7.49-7.55 (m, 1H), 7.81 (s, 2H),7.87 (br. s., 2H), 8.02 (br. s., 1H), 8.05-8.12 (m, 1H), 8.53 (br. s., 1H).

LCMS m/z 565.22 (M+H), Rt 5.30 min., 100% purity.

5-(3′-(cyanomethyl)-2-(isobutylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.83 (d, J=6.44 Hz, 6H), 1.67-1.81 (m, 1H), 2.37 (s, 3H),2.96 (d, J=4.39 Hz, 2H), 4.08 (s, 2H), 7.14-7.25 (m, 2H), 7.26-7.32 (m,1H), 7.35-7.44 (m, 2H), 7.48 (d, J=5.27 Hz, 2H), 7.56 (d, J=7.91 Hz,1H), 7.80 (br. s., 2H), 7.90 (d, J=7.62 Hz, 1H), 8.00 (s, 1H), 8.04-8.13(m, 2H), 8.35 (br. s., 1H), 8.54 (d, J=3.81 Hz, 1H). LCMS m/z 560.23(M+H), Rt 4.67 min., 91.5% purity.

N3′-ethyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-N2-isobutylbiphenyl-2,3′-dicarboxamide

LCMS m/z 592.26 (M+H), Rt 4.28 min., 94.1% purity.

2-(4-fluorophenyl)-5-(4-(furan-3-yl)-3-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR δ ppm 0.86-1.03 (m, 6H), 1.80-1.94 (m, 1H), 2.37 (s, 3H),2.92-3.00 (m, 2H), 6.79 (s, 1H), 7.15-7.24 (m, 2H), 7.28 (d, J=7.03 Hz,2H), 7.35-7.42 (m, 1H), 7.69 (t, J=7.91 Hz, 2H), 7.73-7.85 (m, 3H), 7.94(d, J=19.33 Hz, 1H), 8.04-8.12 (m, 1H), 8.41-8.48 (m, 1H), 8.53 (d, 1H).

LCMS m/z 511.17 (M+H), Rt 4.69 min., 86.5% purity.

3′-phenyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-N2-isobutylbiphenyl-2,3′-dicarboxamide

¹H NMR δ ppm 0.75 (d, J=6.74 Hz, 6H), 1.59-1.72 (m, 1H), 2.37 (s, 3H),2.94-2.98 (m, 2H), 7.15-7.24 (m, 3H), 7.25-7.33 (m, 2H), 7.34-7.47 (m,4H), 7.49-7.58 (m, 2H), 7.63-7.74 (m, 2H), 7.75-7.83 (m, 3H), 7.89 (br.s., 1H), 8.00 (s, 1H), 8.07 (br. s., 1H), 8.54 (br. s., 1H). LCMS m/z597.27 (M+H), Rt 5.74 min., 80% purity.

The general procedures (for amide formations) below pertain to theexperimental procedures. Some of the compounds were made with differentscales of the acids. The acid (0.075 mmol, 1 eq.) was dissolved in driedDMF and followed by adding HATU (0.090 mmol, 1.2 eq.) and DIPEA (0.225mmol, 3.0 eq.). The solution was stirred for 2 minutes and added intoamine (0.090 mmol, 1.2 eq.) at room temperature. The mixture was stirred14 h and purified by prep-HPLC.

2-(4-fluorophenyl)-N-methyl-5-(3-(3-methylbenzylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 9.15 (1H, t, J=5.86 Hz), 8.48 (1H,d, J=4.69 Hz), 8.27 (2H, d, J=4.69 Hz), 8.00-8.08 (1H, m), 7.92-7.97(2H, m), 7.89 (1H, d, J=7.62 Hz), 7.77 (2H, s), 7.61 (1H, t, J=7.62 Hz),7.37 (2H, t, J=8.50 Hz), 7.24 (1H, t, J=7.32 Hz), 7.14-7.22 (2H, m),7.08 (1H, d, J=7.03 Hz), 4.54 (2H, d, J=5.86 Hz), 2.92 (3H, d, J=4.10Hz), 2.34 (3H, s).

2-(4-fluorophenyl)-N-methyl-5-(3-(neopentylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 8.44-8.51 (m, 2H), 8.27 (s, 1H),8.20 (s, 1H), 8.02-8.07 (m, 1H), 7.96 (s, 1H), 7.88 (t, J=7.32 Hz, 2 H),7.77 (s, 2H), 7.59 (t, J=7.62 Hz, 1H), 7.37 (t, J=8.50 Hz, 2H), 3.20 (d,J=6.44 Hz, 2H), 2.92 (d, J=4.69 Hz, 3H), 0.98 (s, 9H).

2-(4-fluorophenyl)-N-methyl-5-(3-(4-methylbenzylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 9.14 (t, J=5.86 Hz, 1H), 8.48 (d,J=4.69 Hz, 1H), 8.27 (s, 1H), 8.25 (s, 1H), 8.01-8.06 (m, 1H), 7.95 (s,1H), 7.93 (d, J=7.62 Hz, 1H), 7.89 (d, J=7.62 Hz, 1H), 7.77 (s, 2H),7.61 (t, J=7.62 Hz, 1H), 7.37 (t, J=8.50 Hz, 2H), 7.27 (d, J=7.62 Hz,2H), 7.16 (d, J=7.62 Hz, 2H), 4.52 (d, J=5.86 Hz, 2 H), 2.92 (d, J=4.10Hz, 3H), 2.30-2.35 (m, 3H).

HPLC purity was determined using a Waters LCT Mass Spectrometer withfour way MUX source analytical LC at 220 nm with employing acetonitrileand water or Waters ZQ with ESCi mass spectrometer. A=5:95 CH₃CN: Water;B=95:5 CH₃CN:Water; Modifier=10 mM NH₄OAc. Retention time was recordedin minutes.

Analytical Method A:

Column Waters Xterra 2.1×50 mm 5 um C18

Time B % Flow 0.00 0 1.0 4.00 100 1.0 5.00 100 1.0

Analytical Method B:

Column: Waters Xbridge 2.1×50 mm 5 um C18

Time B % Flow 0.00 0 1.0 4.00 100 1.0 5.00 100 1.0 5.05 100 1.0 6.00 01.0

Analytical Method C:

Column: Waters Xbridge 4.6×50 mm 5 um C18

Time B % Flow 0.00 0 2.0 8.00 100 2.0 9.00 100 2.0

Analytical Method D

Column: Waters Xbridge 4.6×50 mm 5 um C18

Time B % Flow 0.00 0 1.0 8.00 100 1.0 9.00 100 1.0 9.10 100 1.0 1.00 010

Analytical Method E

Waters ZQ with ESCi mass spectrometer

Column: Supelcu Ascentis 4.6×50 mm 2.7 um C18

Time B % Flow 0.00 10 3.00 5.30 95 3.00 6.00 95 3.00 6.20 10 3.00 7.0010 3.00

Analytical Method F

Waters ZQ with ESCi mass spectrometer

Column: Phenomenex Gemini 4.6×150 mm 3 um C18

Time B % Flow 0.00 10 1.0 10.00 95 1.0 13.00 95 1.0 13.50 10 1.0 15.0010 1.0

Obs. MS HPLC Structure HPLC Rt % Purity Ion Method

2.81 100 458.93 Method A

2.75 100 494.89 Method A

2.38 100 468.9 Method A

2.22 100 472.91 Method A

2.46 100 482.9 Method A

2.68 95.0177 493.92 Method A

2.5 98.5972 494.9 Method A

2.42 100 460.91 Method A

2.34 100 494.9 Method A

3.05 100 472.96 Method A

2.48 100 426.91 Method A

2.86 100 513.92 Method A

2.89 100 513.91 Method A

2.69 100 456.95 Method A

2.8 100 495.94 Method A

2.84 100 513.93 Method A

2.85 100 498.9 Method A

2.56 100 486.94 Method A

2.1 100 458.91 Method A

2.93 100 509.94 Method A

2.53 100 504.9 Method A

2.23 100 485.92 Method A

2.11 100 473.91 Method A

2.51 100 460.92 Method A

2.89 100 458.94 Method A

2.62 100 459.94 Method A

2.85 100 475.95 Method A

2.72 100 444.94 Method A

2.91 100 475.95 Method A

2.97 100 509.93 Method A

2 100 473.92 Method A

2.89 100 475.95 Method A

2.43 100 486.93 Method A

2.44 100 485.85 Method A

2.39 100 856.65 Method B

2.81 96.6226 494.8 Method B

2.75 100 940.66 Method B

2.89 99.0179 988.56 Method B

2.7 100 1056.6 Method B

2.94 89.8624 968.67 Method B

2.75 100 984.61 Method B

2.29 100 455.82 Method B

2.92 98.0936 980.59 Method B

2.32 98.0376 479.8 Method B

2.35 100 472.83 Method B

2.56 100 972.64 Method B

2.26 100 472.83 Method B

2.06 98.6458 892.65 Method B

2.43 100 884.66 Method B

2.81 100 940.69 Method B

2.82 100 940.7 Method B

2.93 100 968.72 Method B

2.95 100 968.7 Method B

2.6 100 884.67 Method B

2.35 100 856.66 Method B

2.34 96.8795 958.6 Method B

2.26 100 479.81 Method B

2.82 100 806.66 Method B

2.75 100 970.55 Method B

2.48 100 480.8 Method B

2.77 100 479.81 Method B

2.7 98.233 480.8 Method B

2.57 100 465.64 Method B

2.85 97.8741 958.25 Method B

2.64 100 930.26 Method B

2.24 100 972.33 Method B

5.21 100 444.95 Method C

4.95 100 444.96 Method C

3.74 100 499.93 Method C

4.54 100 507.94 Method C

4.37 100 507.93 Method C

4.32 100 460.91 Method C

3.68 100 485.94 Method C

5.31 100 510.91 Method C

3.78 100 432.93 Method C

4.68 93.1925 466.91 Method D

5.72 96.6697 464.93 Method D

5.57 96.8314 489.9 Method D

5.72 94.0943 478.93 Method D

4.93 94.4826 455.9 Method D

5.26 88.6355 469.92 Method D

4.7 100 466.92 Method D

5.59 97.7461 494.92 Method D

4.06 100 497.98 Method D

5.05 97.6492 502.96 Method D

4.7 100 474.95 Method D

4.7 100 501.98 Method D

3.74 100 512.96 Method D

5.2 97.5131 486.97 Method D

5.05 100 488.95 Method D

4.74 100 508.95 Method D

4.79 100 482.96 Method D

4.18 100 490.94 Method D

4.8 100 474.98 Method D

4.43 100 499.97 Method D

4.04 95.8428 481.93 Method D

4.5 93.8873 487.97 Method D

4.26 100 490.94 Method D

4.88 100 488.93 Method D

5.11 100 488.97 Method D

4.81 100 522.93 Method D

5.06 100 520.93 Method D

5.74 100 516.94 Method D

4.26 100 473.94 Method D

5.85 100 504.94 Method D

4.69 100 474.96 Method D

4.74 100 479.92 Method D

4.71 100 493.93 Method D

4.19 100 513.95 Method D

5.04 100 488.97 Method D

4.97 100 488.96 Method D

4.7 98.2446 519.93 Method D

5.64 100 522.94 Method D

5.97 100 487 Method D

6.1 100 520.96 Method D

3.168 100 455.14 Method E

2.754 100 461.15 Method E

3.53 95.5615 499.12 Method E

4.061 100 501.23 Method E

3.539 98.8021 459.19 Method E

3.496 100 523.18 Method E

3.008 100 506.17 Method E

3.896 98.8111 539.22 Method E

3.608 100 537.21 Method E

3.868 98.488 557.22 Method E

3.179 100 472.1 Method E

2.536 100 488.16 Method E

2.718 100 502.19 Method E

3.025 100 557.15 Method E

2.664 100 513.16 Method E

2.835 100 514.17 Method E

2.87 100 538.16 Method E

8.435 100 423.19 Method F

8.778 100 490.13 Method F

The general procedures below pertain to the experimental procedures.Some of the compounds were made with different scales.2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (0.100 mmol, 1 eq.) was dissolved in dried1,4-Dioxane (1 mL) and added into Biotage microwave vial (0.5-2 mL)containing boronic acid (0.340 mmol, 3.4 eq.). Then Cs₂CO₃ (0.300 mmol,3 eq.) was added as a solid and following by adding water (0.25 mL). Thevial was flushed with nitrogen and Pd(PPh₃)₄ was added. After the vialwas re-flushed with nitrogen and caped, it was heated in a Biotagemicrowave reactor at 150° C. for 15 minutes. The mixture was filteredwith a 0.45 um filter and dried with a SpeedVac. The sample wasdissovled in DMF (1.6 mL) and purified by prep-HPLC.

5-(3-acetamidophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 10.03 (br. s., 1H), 8.49 (d,J=4.69 Hz, 1H), 8.28 (s, 1H), 8.03 (dd, J=8.79, 5.27 Hz, 2H), 7.93 (br.s., 1H), 7.84 (s, 1 H), 7.75 (d, J=8.20 Hz, 1H), 7.64 (d, J=6.44 Hz,2H), 7.29-7.45 (m, 3H), 2.92 (s, 3 H), 2.12 (s, 3H).

5-(2-(benzyloxy)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 8.41 (d, J=4.69 Hz, 1H), 8.28 (s,1H), 8.03 (dd, J=8.79, 5.27 Hz, 2H), 7.82 (s, 1H), 7.67 (d, J=8.20 Hz,1H), 7.55 (d, J=7.03 Hz, 1H), 7.34-7.47 (m, 7H), 7.13 (d, J=9.37 Hz,1H), 6.83-6.94 (m, 1H), 5.19 (s, 2H), 2.88 (d, J=4.10 Hz, 3H).

2-(4-fluorophenyl)-5-(4-isobutoxyphenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 8.46 (d, J=4.69 Hz, 1H), 8.28 (s,1H), 8.04 (dd, J=8.50, 5.57 Hz, 1H), 7.81 (s, 1H), 7.67-7.73 (m, 1H),7.60-7.67 (m, 2H), 7.36 (t, J=8.79 Hz, 1H), 7.05 (d, J=8.79 Hz, 2H),3.83 (d, J=6.44 Hz, 2 H), 2.91 (d, J=4.69 Hz, 3H), 2.09 (ddd, J=13.33,6.59, 6.44 Hz, 1H), 1.05 (d, J=7.03 Hz, 6H).

HPLC purity was determined using a Waters LCT Mass Spectrometer withfour way MUX source analytical LC at 220 nm with employing acetonitrileand water or Waters ZQ with ESCi mass spectrometer. A=5:95 CH₃CN:Water;B=95:5 CH₃CN:Water; Modifier=10 mM NH₄OAc. Retention time was recordedin minutes.

Analytical Method A:

Column Waters Xterra 2.1×50 mm 5 um C18

Time B % Flow 0.00 0 1.0 4.00 100 1.0 5.00 100 1.0

Analytical Method B:

Column: Waters Xbridge 2.1×50 mm 5 um C18

Time B % Flow 0.00 0 1.0 4.00 100 1.0 5.00 100 1.0 5.05 100 1.0 6.00 01.0

Analytical Method F

Waters ZQ with ESCi mass spectrometer

Column: Phenomenex Gemini 4.6×150 mm 3 um C18

Time B % Flow 0.00 10 1.0 10.00 95 1.0 13.00 95 1.0 13.50 10 1.0 15.0010 1.0

Obs. MS HPLC Structure HPLC Rt % Purity Ion Method

7.23 100 390.16 Method F

3.842 100 460.23 Method F

7.666 100 416.18 Method F

7.018 100 403.2 Method F

5.322 100 336.23 Method F

7.091 100 396.13 Method F

12.982 100 470.3 Method F

13.755 100 418.33 Method F

12.669 100 446.26 Method F

10.775 100 395.28 Method F

8.933 100 439.24 Method F

10.716 100 395.31 Method F

11.858 100 461.33 Method F

10.916 100 399.21 Method F

2.49 100 443.06 Method B

2.56 100 410 Method B

2.36 100 376.05 Method B

2.75 90.0925 457.45 Method B

2.36 95.5596 447.39 Method B

3.34 100 446.41 Method B

2.43 100 417.4 Method B

2.67 97.2446 445.4 Method B

2.37 100 417.33 Method B

2.02 100 416.3 Method B

2.92 100 471.37 Method B

2.76 100 445.37 Method B

2.71 100 457.35 Method B

2.52 100 431.35 Method B

2.725 94.4043 445.36 Method B

2.38 95.3608 442.32 Method B

2.56 100 431.34 Method B

2.76 97.5284 445.38 Method B

The general procedures below pertain to the experimental procedures.2-(4-fluorophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide (0.120mmol, 1 eq.) in THF (2.3 mL) was added into Biotage microwave vial (5mL) containing ROH (2.28 eq.) and PPh₃ (1.4 eq.). Then DEAD (1.4 eq.)was added as neat. The vial was flushed with nitrogen, caped and heatedat 140° C. for 20 minutes in a Biotage microwave reactor. The mixturewas dried with SpeedVac, dissolved in DMF (1.6 mL) and purified byprep-HPLC.

5-(2-(4-tert-butylphenoxy)ethoxy)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d₆-CDCl₃) δ ppm 8.36 (d, J=4.69 Hz, 1H), 8.27 (s,1H), 7.99 (dd, J=8.50, 5.57 Hz, 1H), 7.56 (d, J=8.79 Hz, 1H), 7.28-7.39(m, 3H), 7.21 (d, J=2.34 Hz, 1H), 7.05 (dd, J=9.37, 2.34 Hz, 1H), 6.94(d, J=8.79 Hz, 3H), 4.28-4.45 (m, 4H), 2.89 (d, J=4.69 Hz, 3H), 1.30 (s,9H).

HPLC purity was determined using a Waters LCT Mass Spectrometer withfour way MUX source analytical LC at 220 nm with employing acetonitrileand water. A=5:95 CH₃CN:Water; B=95:5 CH₃CN:Water; Modifier=10 mMNH₄OAc. Retention. Time was recorded in minutes.

Analytical Method B:

Column: Waters Xbridge 2.1×50 mm 5 um C18

Time B % Flow 0.00 0 1.0 4.00 100 1.0 5.00 100 1.0 5.05 100 1.0 6.00 01.0

Obs. MS HPLC Structure HPLC Rt % Purity Ion Method

3.63 100 461.8073 Method B

2.81 100 442.825 Method B

The general procedures below pertain to the experimental procedures.4-[2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl]-2-(isobutylcarbamoyl)phenyltrifluoromethanesulfonate (0.076 mmol, 45 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (6.24 mg,0.02 mmol), boronic acid (0.175 mmol) and potassium phosphate (0.190mmol, 40.2 mg) were added into Biotage microwave vial (5 mL), andfollowed by adding dioxane (3 mL) and water (0.3 mL). The vial wasflushed with nitrogen and Pd(OAc)₂ (0.076 mmol, 1.7 mg) was added. Thevial was heated in a Biotage Initiator at 110° C. for 10 minutes anddried with a SpeedVac-250 at 40° C. overnight. The samples weredissolved in DMF-MeOH, filtered via a plate with filters, and purifiedby prep-HPLC

Prep-HPLC: Dionex APS-30000, UV 220 nm, Column: Waters Xbridge 19×200mm, 5 um, C18. Solvents: A=Water, 20 mM NH₄OH, B=Acetonitrile)

Analytical Method A:

Waters LCT mass spectrometer with 4 way MUX source.

LC Conditions

Column: Ascentis 4.6×50 mm 5 um C18

Mobile Phase A=5:95 MeCN:Water; B=95:5 MeCN:Water; Modifier=10 mMNH₄OAc. Retention Time Rt was recorded in minutes.

Time B % Flow 0.00′ 0 2.0 8.00′ 100 2.0 9.00′ 100 2.0

HPLC Obs. MS HPLC Structure Rt % Purity Ion Method

5.77 96 569.286 Method A

4.86 95 536.2426 Method A

5.20 97 536.26428 Method A

5.93 100 557.2553 Method A

The following examples/intermediates were prepared by the Suzukicoupling of the corresponding benzofuran-5-yl trifluoromethanesulfonatewith 3-boronic acid (or ester) of the corresponding benzoic acid, andthe acid intermediate obtained was coupled to cyclopropylamine asdescribed before.

3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=404.04, HPLCR_(t)=1.728 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC first using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=0, Final % B=100, Gradient time=10 min, Stop time=12 min,Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 8.80-9.26 min. (UV detection at 220 nm). The desiredfractions collected were evaporated and the white solid obtained waspurified again by the same method except with Start % B=50, Final %B=100, Fraction Collection: 5.34-6.15 min. ¹H NMR (500 MHz, CD₃OD) δ8.61 (d, J=5.80, 1H), 8.44 (t, J=7.32, 1H), 7.97 (dd, J=8.85, 5.19, 2H),7.87 (s, 1H), 7.85 (d, J=6.71, 1H), 7.83-7.81 (m, 2H), 7.67 (d, J=8.24,1H), 7.64 (d, J=0.92, 1H), 7.47 (d, J=8.55, 1H), 7.38 (dd, J=8.39, 1.68,1H), 7.29 (t, J=8.85, 2H), 2.95 (s, 3H), 2.36 (s, 3H), 1.82 (m, 2H),1.75 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument withUV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=520.41, HPLCR_(t)=1.513 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=8.90 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=9.43 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl, R_(t)=13.20 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-4-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 5.07-5.88 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.68 (d, J=7.32, 1H), 7.97 (dd, J=8.85, 5.19, 2H), 7.87 (d,J=2.14, 1H), 7.86 (m overlapped with d, 1H), 7.81 (d, J=7.02, 1H), 7.67(d, J=8.55, 1H), 7.65 (d, J=1.22, 1H), 7.48 (d, J=8.55, 1H), 7.39 (dd,J=8.39, 1.68, 1H), 7.28 (t, J=8.85, 2H), 2.95 (s, 3H), 2.37 (s, 3H),1.83 (appeared as d, 4H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=520.15, HPLC R_(t)=1.435 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R _(t)=8.03 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm (Start % B=10, Final % B=100), R_(t)=14.09 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC first using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 5.05-5.76 min. (UV detection at 220 nm). The desiredfractions collected were evaporated and the residue obtained waspurified again by the same method except with Start % B=10, Final %B=100, Fraction Collection: 8.74-9.27 min. ¹H NMR (500 MHz, CD₃OD) δ8.76 (d, J=2.44, 1H), 8.71 (dd, J=5.80, 0.92, 1H), 8.50 (ddd, J=8.32,2.21, 1.37, 1H), 8.04 (dd, J=8.39, 5.65, 1H), 7.96 (dd, J=9.00, 5.34,2H), 7.83 (d, J=1.53, 1H), 7.82 (m overlapped with d, 1H), 7.66 (d,J=8.24, 1H), 7.64 (d, J=1.83, 1H), 7.45 (d, J=8.55, 1H), 7.28 (t,J=8.70, 2H), 2.95 (s, 3H), 2.35 (s, 3H), 1.60 (appeared as td, J=4.20,2.59, 4H). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=520.08, HPLCR_(t)=1.482 min.

2-(4-Fluorophenyl)-5-(5-(1-(4-fluorophenyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 9.08-9.63 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.97 (dd, J=8.85, 5.19, 2H), 7.78-7.77(overlapping m, 2H), 7.65 (d, J=8.55, 1H), 7.63 (d, J=1.22, 1H), 7.41(d, J=8.55, 1H), 7.37-7.33 (overlapping m, 3H), 7.28 (t, J=8.85, 2H),7.01 (t, J=8.85, 2H), 2.95 (s, 3H), 2.33 (s, 3H), 1.32 (m, 4H). LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=537.08, HPLC R_(t)=1.840 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=10.20 min;Column: Xbridge Phenyl 3.5 um, 4.6×150 mm (Start % B=10, Final % B=100),R_(t)=8.16 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=14.20 min.

4-Chloro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=424.26, 426.25, HPLCR_(t)=1.763 min.

5-(2-Chloro-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC first using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 6.02-6.54 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.62 (dd, J=5.80, 0.61, 1H), 8.44 (td, J=7.93, 1.53 1H), 8.04(d, J=2.44, 1H), 7.96 (dd, J=8.85, 5.19, 2H), 7.93 (dd, J=8.39, 2.291H), 7.84-7.81 (overlapping m, 2H), 7.76 (d, J=1.83, 1H), 7.69 (d,J=2.44, 1H), 7.67 (d, J=2.75, 1H), 7.50 (dd, J=8.55, 1.53, 1H), 7.28 (t,J=8.70, 2H), 2.95 (s, 3H), 1.83 (m, 2H), 1.76 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=540.33, 542.33, HPLCR_(t)=1.568 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=9.19 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=9.89 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl, R_(t)=16.19 min.

5-(2-Chloro-5-(1-(3-methoxyphenyl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC first usingthe separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=70, Final % B=100, Gradienttime=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.61-7.41 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 7.97 (dd, J=8.70, 5.34,2H), 7.94 (d, J=2.14, 1H), 7.85 (dd, J=8.39, 1.98, 1H), 7.76 (s, 1H),7.65 (dd, J=12.51, 8.55, 2H), 7.49 (dd, J=8.55, 1.53, 1H), 7.28 (t,J=8.70, 2H), 7.20 (t, J=7.93, 1H), 6.87 (s, 1H), 6.85 (m overlapped withs, 1H), 6.75 (dd, J=8.70, 1.68, 1H), 3.77 (s, 3H), 2.95 (s, 3H), 1.34(appeared as d, 4H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=569.39, HPLC R_(t)=1.858 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=10.33 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=7.96 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, Rt=14.80 min.

5-(2-Chloro-5-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-ylcarbonyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC first usingthe separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=70, Final % B=100, Gradienttime=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.88-8.49 min. (UVdetection at 220 nm). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=595.39, HPLC R_(t)=1.952 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=11.75 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=8.68 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, R_(t)=15.85 min.

5-(5-Amino-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The Suzuki coupling with4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline wasperformed by using: dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine(S-Phos), Pd(OAc)₂, K₂CO₃, (1:2 H₂O/1,4-dioxane, 90° C.). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=375.22, HPLC R_(t)=1.362 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropanecarboxamido)phenyl)benzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC first usingthe separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradienttime=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 10.05-10.51 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 7.97 (dd, J=8.85, 5.49,2H), 7.60 (d, J=8.55, 1H), 7.55 (d, J=1.53, 1H), 7.52 (dd overlappedwith s, 1H), 7.51 (s, 1H), 7.44 (t, J=7.48, 2H), 7.36 (m, 1H), 7.30 (ddoverlapped with m, J=1.53, 1H), 7.29-7.27 (overlapping m, 3H), 7.25 (d,J=2.14, 1H), 7.21 (appeared as d, 1H), 2.95 (s, 3H), 2.21 (s, 3H), 1.60(m, 2H), 1.19 (m, 2H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+Na)⁺=541.36, HPLC R_(t)=1.952 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=12.49 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=9.11 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, R_(t)=15.98 min.

4-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=453.93, HPLCR_(t)=1.757 min.

5-(2-Chloro-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 6.00-6.58 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.61 (d, J=5.80, 1H), 8.42 (td, J=8.01, 1.68, 1H), 7.99 (s,1H), 7.96 (m, J=8.85, 5.19, 2H), 7.87 (d, J=8.24, 1H), 7.79 (ddd,J=7.40, 6.03, 0.92, 1H), 7.69 (d, J=1.83, 1H), 7.64 (d, J=8.55, 1H),7.44 (dd, J=8.55, 1.83, 1H), 7.40 (s, 1H), 7.27 (t, J=8.85, 2H), 4.10(s, 3H), 2.95 (s, 3H), 1.84 (m, 2H), 1.75 (m, 2H). LC/MS were performedby using Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18,3.0×50 mm; (ES+) m/z (M+H)⁺=569.90, 570.79, 571.82, HPLC R_(t)=1.592min. Analytical HPLC were performed by using Shimadzu-VP instrument withUV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=9.56 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=9.97 min. Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=10, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=16.35 min.

Methyl1-(4-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzamido)cyclopropanecarboxylate

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=551.02, HPLCR_(t)=1.753 min.

4-Chloro-2-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=441.91, HPLCR_(t)=1.803 min.

5-(2-Chloro-4-fluoro-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 5.63-6.40 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.60 (d, J=5.49, 1H), 8.34 (td, J=7.93, 1.83, 1H), 7.97 (m,J=8.85, 5.19, 2H), 7.90 (d, J=7.63, 1H), 7.83 (d, J=8.24, 1H), 7.73(overlapping, 2H), 7.68 (d, J=8.54, 1H), 7.56 (d, J=10.38, 1H), 7.47(dd, J=8.55, 1.83, 1H), 7.29 (t, J=8.70, 2H), 2.95 (s, 3H), 1.82 (m,2H), 1.70 (m, 2H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z(M+H)⁺=558.04, HPLC Rt=1.558 min. Analytical HPLC were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA, SolventB=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18,3.5 um, 4.6×150 mm, R_(t)=3.10 min; Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=3.60 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=13.24 min.

5-(5-(tert-Butylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.62-9.21 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=8.85, 5.49, 2H), 7.67 (doverlapping with s, 1H), 7.67 (s, 1H), 7.65 (d, J=8.55, 1H), 7.63 (d,J=1.22, 1H), 7.38 (d overlapping with dd, 1H), 7.37 (dd, J=1.53, 1H),7.28 (t, J=8.70, 2H), 2.96 (s, 3H), 2.32 (s, 3H), 1.47 (s, 9H). LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=459.31, HPLC R_(t)=1.763 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=17.08 min;Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=14.81 min.

5-(5-(1-Cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.13-7.85 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=8.70, 5.34, 2H), 7.77 (doverlapping with s, 1H), 7.76 (s, 1H), 7.66 (d, J=8.24, 1H), 7.63 (d,J=1.53, 1H), 7.44 (d, J=8.24, 1H), 7.37 (dd, J=8.39, 1.68, 1H), 7.28 (t,J=8.85, 2H), 2.95 (s, 3H), 2.34 (s, 3H), 1.59 (m, 2H), 1.36 (m, 2H).LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=468.28, HPLCR_(t)=1.633 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=14.21 min; Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=12.79 min.

Methyl1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarboxylate

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.26-7.97 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=8.85, 5.19, 2H), 7.77 (dd,J=4.27, 2.14, 2H), 7.66 (d, J=8.55, 1H), 7.63 (d, J=1.22, 1H), 7.42 (d,J=8.55, 1H), 7.37 (dd, J=8.39, 1.68, 1H), 7.28 (t, J=8.85, 2H), 3.71 (s,3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.59 (m, 2H), 1.26 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=501.23, HPLC R_(t)=1.657 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.81 min; XbridgePhenyl 3.5 um, 4.6×150 mm, R_(t)=5.58 min. Analytical HPLC method:Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mMNH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, R_(t)=12.48 min.

2-(4-Fluorophenyl)-5-(5-(1-(hydroxymethyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.78-9.06 min. (UV detection at 220nm). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=473.33, HPLCR_(t)=1.827 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(prop-2-ynylcarbamoyl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.43-7.91 min. (UV detection at 220nm). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=524.21, HPLCRt=1.642 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(2-methyl-1-morpholinopropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=20, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 7.64-8.27 min. (UV detection at 220 nm). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=544.38, HPLC R_(t)=1.503 min.

5-(5-(2-Cyclopropylpropan-2-ylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 9.21-9.86 min. (UV detection at 220 nm). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=485.34, HPLC R_(t)=1.842 min.

5-(2-Cyclopropyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 6.26-6.59 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.54 (d, J=5.19, 1H), 8.17 (m, 1H), 7.98 (m, J=8.85, 5.19, 2H),7.87-7.86 (overlapped m, 2H), 7.77 (d, J=1.53, 1H), 7.69 (d overlappedwith d, 1H), 7.68 (d, J=8.24, 1H), 7.58 (m, 1H), 7.50 (dd, J=8.55, 1.83,1H), 7.29 (t, J=8.85, 2H), 7.11 (d, J=8.55, 1H), 2.96 (s, 3H), 1.98 (m,1H), 1.77 (m, 2H), 1.61 (m, 2H), 0.96 (m, 2H), 0.82 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=546.04, HPLC R_(t)=1.603 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=9.71 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=10.26 min. Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=13.95 min.

Ethyl2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylate

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=579.41, HPLCR_(t)=2.032 min.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

A mixture of5-(2-chloro-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(62.7 mg, 0.11 mmol, crude),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (52.4 mg, 0.11mmol), MeBF₃K (20.12 mg, 0.165 mmol), diacetoxypalladium (12.35 mg,0.055 mmol) and potassium carbonate (76 mg, 0.550 mmol) in a mixture ofH₂O (0.2 mL)/THF (2 mL) was stirred at 90° C. under N₂ for 6 hours 30min. The mixture was left standing at r.t. overnight, and then dilutedwith MeOH and filtered through a Whatman 0.45 um PVDF with GMF disk. Thefiltrate was purified by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=70, Final % B=90,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 2.26-2.77 min. (UVdetection at 220 nm) to obtain the product as a TFA salt. ¹H NMR (500MHz, CD₃OD) δ 8.60 (d, J=5.80, 1H), 8.41 (m, 1H), 7.96 (m, J=9.00, 5.34,2H), 7.87 (s, 1H), 7.85 (d, J=9.00, 1H), 7.79 (t, J=6.56, 1H), 7.64 (d,J=8.24, 1H), 7.58 (d, J=1.53, 1H), 7.33 (dd, J=8.55, 1.83, 1H), 7.17 (s,1H), 7.28 (t, J=8.85, 2H), 4.09 (s, 3H), 2.95 (s, 3H), 2.38 (s, 3H),1.84 (m, 2H), 1.75 (m, 2H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=550.00, HPLC R_(t)=1.588 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=9.12 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=9.82 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=13.46 min.

5-(4-Fluoro-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC twice using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 5.58-5.94 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.57 (d, J=5.49, 1H), 8.26 (td, J=7.93, 1.53, 1H), 7.97 (m,J=9.16, 5.19, 2H), 7.79 (d, J=8.24, 1H), 7.73 (d, J=7.63, 1H), 7.67 (d,J=8.55, 1H), 7.65 (m overlapping with d, 1H), 7.62 (d, J=1.83, 1H), 7.35(dd, J=8.39, 1.68, 1H), 7.29 (t, J=8.85, 2H), 7.25 (d, J=11.90, 1H),2.95 (s, 3H), 2.35 (s, 3H), 1.80 (m, 2H), 1.66 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=538.04, HPLCR_(t)=1.497 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=9.46 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=9.66 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=12.95 min.

5-(4-Fluoro-2-hydroxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

5-(4-Fluoro-2-hydroxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamidewas obtained as a side product during the synthesis of5-(4-fluoro-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide.The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC twice using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 4.16-4.55 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.55 (broad d, J=3.66, 1H), 8.19 (t, J=7.78, 1H), 7.97 (m,J=8.85, 5.19, 2H), 7.86 (d, J=8.54, 1H), 7.82 (s, 1H), 7.74 (d, J=8.24,1H), 7.61 (t overlapping with dd, 1H), 7.58 (dd, 2H), 7.28 (t, J=8.70,2H), 6.79 (d, J=12.51, 1H), 2.97 (s, 3H), 1.78 (appeared as s, 2H), 1.63(appeared as s, 2H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=540.07, HPLC R_(t)=1.342 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=8.06 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=8.56 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=13.91 min.

2-(4-Fluorophenyl)-5-(2-hydroxy-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

2-(4-Fluorophenyl)-5-(2-hydroxy-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamidewas obtained as a side product from a similar reaction. Purification byShimadzu-VP preparative reverse phase HPLC twice using the separationmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stoptime=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5,Fraction Collection: 7.79-8.24 min. (UV detection at 220 nm). ¹H NMR(500 MHz, CD₃OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.91 (d, J=2.14, 1H),7.88 (d, J=1.53, 1H), 7.76 (dd, J=8.55, 2.14, 1H), 7.65-7.61(overlapping m, 2H), 7.29-7.27 (overlapping m, 6H), 7.16 (m, 1H), 7.00(d, J=8.55, 1H), 2.97 (s, 3H), 1.35 (m, 4H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18,3.0×50 mm; (ES+) m/z (M+H)⁺=521.28, HPLC R_(t)=1.695 min. AnalyticalHPLC were performed by using Shimadzu-VP instrument with UV detection at220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95%H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.84 min; Column: XbridgePhenyl 3.5 um, 4.6×150 mm, R_(t)=5.71 min. Analytical HPLC method:Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mMNH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min, Column: Xbridge Phenyl, R_(t)=12.68 min.

Methyl1-(5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzamido)cyclopropanecarboxylate

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.07-8.45 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, 2H), 7.85 (s, 1H), 7.63 (d,J=8.55, 1H), 7.58 (d, J=1.22, 1H), 7.33 (dd, J=8.55, 1.83, 1H), 7.27 (t,J=8.85, 2H), 7.11 (s, 1H), 4.03 (s, 3H), 3.71 (s, 3H), 2.96 (s, 3H),2.35 (s, 3H), 1.61 (m, 2H), 1.28 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=531.23, HPLC R_(t)=1.715 min.

4-Cyclopropyl-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

4-Cyclopropyl-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid was prepared in a similar manner as described by using potassiumcyclopropyltrifluoroborate. LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=430.07, HPLC R_(t)=1.802 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

A mixture of methyl1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarboxylate(25.3 mg, 0.051 mmol), N′-hydroxyacetimidamide (11.23 mg, 0.152 mmol)and K₂CO₃ (41.9 mg, 0.303 mmol) in toluene (1 mL) under N₂ in are-usable sealed tube was stirred at 150° C. for two hours. The mixturewas evaporated, diluted with MeOH and purified by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 7.54-8.08 min. (UV detection at 220 nm), to give the productas a white solid (19.9 mg, 75%). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m,J=9.00, 5.34, 2H), 7.82 (d, J=2.14, 1H), 7.81 (overlapping m, 1H), 7.66(d, J=8.55, 1H), 7.65 (d, J=1.50, 1H), 7.44 (d, J=8.55, 1H), 7.38 (dd,J=8.24, 1.83, 1H), 7.28 (m, J=8.85, 2H), 2.95 (s, 3H), 2.36 (s, 3H),2.31 (s, 3H), 1.75 (m, 2H), 1.58 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=525.12, HPLC R_(t)=1.700 min.

5-(5-(1-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.32-8.92 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=8.85, 5.49, 2H), 7.81 (d,J=1.83, 1H), 7.80 (broad s overlapping with d, 1H), 7.66 (d overlappingwith d, 1H), 7.64 (d, J=1.53, 1H), 7.44 (d, J=8.55, 1H), 7.38 (dd,J=8.39, 1.68, 1H), 7.28 (m, J=8.85, 2H), 2.95 (s, 3H), 2.35 (s, 3H),2.02 (m, 1H), 1.72 (m, 2H), 1.54 (m, 2H), 1.04 (m, 2H), 0.95 (m, 2H).LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=551.09, HPLCR_(t)=1.763 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=8.73 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=6.96 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=13.22 min.

2-(4-Fluorophenyl)-5-(5-(1-(3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.92-8.52 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.82 (d,J=2.14, 1H), 7.81 (t overlapped with d, 1H), 7.66 (d overlapped with d,1H), 7.65 (d, J=1.83, 1H), 7.45 (d, J=8.55, 1H), 7.38 (dd, J=8.55, 1.83,1H), 7.28 (t, J=8.70, 2H), 4.51 (s, 2H), 3.42 (s, 3H), 2.95 (s, 3H),2.36 (s, 3H), 1.79 (m, 2H), 1.60 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=555.23, HPLC Rt=1.700 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=7.11 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.57 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=12.51 min.

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

The product was obtained as a TFA salt after Purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 7.83-8.56 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.71 (d, J=4.88, 1H), 8.19 (d, J=7.93, 1H), 8.08 (td, J=7.78,1.53, 1H), 7.97 (m, J=9.00, 5.34, 2H), 7.85 (s, 1H), 7.84 (m overlappingwith s, 1H), 7.66-7.63 (overlapping m, 3H), 7.45 (d, J=8.55, 1H), 7.38(dd, J=8.55, 1.83, 1H), 7.28 (m, J=8.85, 2H), 2.95 (s, 3H), 2.36 (s,3H), 1.91 (m, 2H), 1.67 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=588.07, HPLC R_(t)=1.728 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R _(t)=6.96 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.83 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=13.15 min.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 7.80-8.36 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.86 (s, 1H),7.63 (d, J=8.55, 1H), 7.59 (d, J=1.83, 1H), 7.33 (dd, J=8.24, 1.83, 1H),7.27 (t, J=8.85, 2H), 7.13 (s, 1H), 4.06 (s, 3H), 2.96 (s, 3H), 2.36 (s,3H), 2.31 (s, 3H), 1.77 (m, 2H), 1.60 (m, 2H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna,3.0×50 mm, S10; (ES+) m/z (M+H)⁺=555.10, HPLC Rt=1.723 min. AnalyticalHPLC were performed by using Shimadzu-VP instrument with UV detection at220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95%H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=5.98 min. AnalyticalHPLC method: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95%MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5um, 4.6×150 mm, R_(t)=12.98 min.

5-(2-Chloro-4-methoxy-5-(1-(3-methyl-1,2,4-oxadiazol-5-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.06-8.56 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.99-7.96 (m overlapping with s, 2H),7.97 (s, 1H), 7.71 (d, J=1.53, 1H), 7.64 (d, J=8.55, 1H), 7.45 (dd,J=8.55, 1.83, 1H), 7.37 (s, 1H), 7.27 (t, J=8.85, 2H), 4.06 (s, 3H),2.96 (s, 3H), 2.32 (s, 3H), 1.78 (m, 2H), 1.61 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=575.08, HPLCR_(t)=1.752 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=8.23 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=6.39 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=13.49 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methyl-4H-1,2,4-triazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

A mixture of5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(33.8 mg, 0.072 mmol), acetohydrazide (16.07 mg, 0.217 mmol) and K₂CO₃(9.99 mg, 0.072 mmol) in n-BuOH (1 mL) under N₂ in a re-usable sealedtube was stirred at 150° C. for four hours. The mixture was diluted withMeOH and purified by Shimadzu-VP preparative reverse phase HPLC usingthe separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradienttime=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 5.93-6.53 min. (UVdetection at 220 nm) to obtain the product as a TFA solvate. ¹H NMR (500MHz, CD₃OD) δ 7.97 (m, J=8.85, 5.49, 2H), 7.85 (s, 1H), 7.85 (moverlapped with s, J=1.83, 1H), 7.66 (d, J=8.55, 1H), 7.64 (d, J=1.22,1H), 7.45 (d, J=7.63, 1H), 7.38 (dd, J=8.39, 1.68, 1H), 7.29 (t, J=8.70,2H), 2.95 (s, 3H), 2.56 (s, 3H), 2.36 (s, 3H), 1.68 (m, 2H), 1.57 (m,2H). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=524.23, HPLCR_(t)=1.545 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=11.80 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=12.13 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3, Rt=11.87 min.

5-(5-(1-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 8.05-8.58 min. (UV detection at 220nm) to obtain the product as a TFA solvate. ¹H NMR (500 MHz, CD₃OD) δ7.97 (m, J=8.85, 5.19, 2H), 7.85 (s, 1H), 7.84 (dd overlapping with s,J=1.83, 1H), 7.67 (d, J=8.24, 1H), 7.64 (d, J=1.53, 1H), 7.45 (d,J=7.63, 1H), 7.38 (dd, J=8.39, 1.68, 1H), 7.29 (t, J=8.85, 2H), 2.95 (s,3H), 2.36 (s, 3H), 2.15 (m, 1H), 1.66 (m, 2H), 1.55 (m, 2H), 1.23 (m,2H), 1.11 (m, 2H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=500.00,HPLC R_(t)=1.598 min. Analytical HPLC were performed by usingShimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA, SolventB=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18,3.5 um, 4.6×150 mm, R_(t)=9.45 min; Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=9.81 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl, R_(t)=15.29 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-phenyl-4H-1,2,4-triazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

Purification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 6.48-7.03 min. (UV detection at 220nm) to obtain the product as a TFA solvate. ¹H NMR (500 MHz, CD₃OD) δ7.99-7.95 (overlapping m, 4H), 7.88-7.85 (overlapping m, 2H), 7.67-7.65(overlapping m, 2H), 7.49-7.45 (overlapping m, 3H), 7.44 (d, J=7.93,1H), 7.39 (dd, J=8.55, 1.53, 1H), 7.28 (t, J=8.70, 2H), 2.95 (s, 3H),2.35 (s, 3H), 1.72 (m, 2H), 1.48 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=585.89, HPLC R_(t)=1.765 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.85 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.81 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl, R_(t)=13.04 min.

2-(4-Fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(43.5 mg, 0.093 mmol) in ethanol (1.5 mL) at r.t. under N₂ was addedhydroxylamine hydrochloride (12.93 mg, 0.186 mmol), followed by Et₃N(0.039 mL, 0.279 mmol). The mixture was stirred at reflux (115° C.) forabout 4 hours. The mixture was cooled to r.t. and evaporated. Theresidue was used for the next step without further purification. LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=501.13, HPLCR_(t)=1.385 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide(46.5 mg, 0.093 mmol, crude) in pyridine (0.5 mL, 6.18 mmol) at r.t.under N₂ was added acetyl chloride (0.020 mL, 0.279 mmol). The mixturewas stirred at 115° C. for 2 hours. The mixture was cooled to r.t.,diluted with MeOH and purified by Shimadzu-VP preparative reverse phaseHPLC using the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column.Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.64-7.95 min. (UVdetection at 220 nm). The residue obtained after evaporation of thecombined fractions was further purified by preparative TLC, 10%MeOH/CH₂Cl₂, two 20 cm×20 cm×0.5 mm plates. Rf about 0.67 (10%MeOH/CH₂Cl₂). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.81(s, 1H), 7.80 ((m overlapped with s, J=2.14, 1H), 7.66 (d, J=8.55, 1H),7.65 (d, J=1.22, 1H), 7.43 (d, J=8.55, 1H), 7.36 (dd, J=8.55, 1.83, 1H),7.28 (m, J=8.70, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H), 1.59 (m,2H), 1.43 (m, 2H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z(M+H)⁺=525.07, HPLC R_(t)=1.682 min. Analytical HPLC were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and 254 nm.Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA, SolventB=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18,3.5 um, 4.6×150 mm, R_(t)=6.67 min; Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=5.22 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=12.36 min.

1-(3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarboxylicacid

¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.78 (s, 1H), 7.77(m overlapping with s, 1H), 7.66 (d, J=8.55, 1H), 7.64 (d, J=1.22, 1H),7.42 (d, J=8.55, 1H), 7.38 (dd, J=8.55, 1.83, 1H), 7.28 (t, J=8.70, 2H),2.96 (s, 3H), 2.34 (s, 3H), 1.60 (m, 2H), 1.25 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=487.27, HPLC R_(t)=1.625 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=5.38 min; XbridgePhenyl 3.5 um, 4.6×150 mm, R_(t)=4.43 min. Analytical HPLC method:Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mMNH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, Rt=10.67 min.

tert-Butyl2-(1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarbonyl)hydrazinecarboxylate

To a mixture of1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarboxylicacid (41.6 mg, 0.086 mmol), tert-butyl hydrazinecarboxylate (16.95 mg,0.128 mmol) and2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate (54.9 mg, 0.171 mmol) in DMF (1 mL) at r.t under N₂was added N,N-diisopropylethylamine (0.060 mL, 0.342 mmol). The mixturewas stirred at r.t. for 19 hours. The mixture was added 5 ml H₂O. Thewhite precipitates were filtered, washed with 3×2 ml H₂O and dried (33.1mg), and was used without further purification. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; HPLC R_(t)=1.750 min.

2-(4-Fluorophenyl)-5-(5-(1-(hydrazinecarbonyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

To tert-butyl2-(1-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)cyclopropanecarbonyl)hydrazinecarboxylate(33.1 mg, 0.055 mmol) in a round-bottom flask at r.t. under N₂ was addedHCl (1 ml, 4.00 mmol, 4 M in 1,4-dioxane). The mixture was stirred atr.t. for four hours. The mixture was evaporated, and the crudehydrochloride salt used without further purification. LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=501.06, HPLCR_(t)=1.483 min.

5-(5-(1-(5-Amino-1,3,4-oxadiazol-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of2-(4-fluorophenyl)-5-(5-(1-(hydrazinecarbonyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide,hydrochloride (29.5 mg, 0.055 mmol, crude) in 1,4-dioxane (1 ml) at r.t.was added a solution of cyanic bromide (58.3 mg, 0.550 mmol) inacetonitrile (0.5 mL), and then sat. aq. NaHCO₃ (0.1 ml). The mixturewas stirred at r.t. for about 5 hours. The mixture was added 0.3 ml 1NHCl, diluted with MeOH and purified by Shimadzu-VP preparative reversephase HPLC using the separation method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.53-7.18 min. (UVdetection at 220 nm) to obtain the product as a TFA salt. ¹H NMR (500MHz, CD₃OD) δ 7.97 (dd, J=8.55, 5.19, 2H), 7.80 (s, 1H), 7.80 ((moverlapped with s, 1H), 7.66 (d, J=8.55, 1H), 7.63 (s, 1H), 7.44 (d,J=8.55, 1H), 7.37 (dd, J=8.24, 1.22, 1H), 7.29 (t, J=8.70, 2H), 2.95 (s,3H), 2.35 (s, 3H), 1.64 (m, 2H), 1.49 (m, 2H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna,3.0×50 mm, S10; (ES+) m/z (M+H)⁺=526.05, HPLC R_(t)=1.577 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=3.23 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=3.39 min. Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=11.04 min.

5-(5-(1-(1H-Tetrazol-5-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(25.1 mg, 0.054 mmol) in DMF (1 mL) at r.t. under N₂ was added ammoniumchloride (8.62 mg, 0.161 mmol), and then sodium azide (6.98 mg, 0.107mmol). The mixture was stirred at 120° C. for about 4 hours. The mixturewas cooled to r.t., and added with another 18 mg of NH₄Cl and then 14 mgof NaN₃. The mixture was stirred at 120° C. for 14.5 hours. The mixturewas cooled to r.t., and added with another 26 mg of NH₄Cl, followed by21 mg of NaN₃. The mixture was re-stirred at 120° C. for 24 hours. Themixture was cooled to r.t., and diluted with MeOH and purified byShimadzu-VP preparative reverse phase HPLC using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 6.82-7.27 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 7.97 (m, J=9.00, 5.34, 2H), 7.85 (d, J=1.22, 1H), 7.84 (ddoverlapping with d, J=1.83, 1H), 7.67 (d, J=8.24, 1H), 7.65 (d, J=1.22,1H), 7.45 (d, J=7.63, 1H), 7.39 (dd, J=8.55, 1.83, 1H), 7.29 (t, J=8.85,2H), 2.95 (s, 3H), 2.36 (s, 3H), 1.70 (m, 2H), 1.58 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column: XterraMS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=511.28, HPLC R_(t)=1.595 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=5.10 min; XbridgePhenyl 3.5 um, 4.6×150 mm, R_(t)=4.23 min. Analytical HPLC method:Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mMNH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3, R_(t)=10.58 min.

2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylicacid

Prepared by the hydrolysis of ethyl2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylate.LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=551.34, HPLCR_(t)=1.895 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxamide

Prepared by the coupling of2-(4-fluorophenyl)-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxylicacid with methylamine hydrochloride under the conditions as described.LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min, Column:Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=564.36, HPLCR_(t)=1.768 min.

6-Amino-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

Obtained as a TFA salt from the reduction of2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-nitrobenzofuran-3-carboxamideusing H₂ with 5% Pd/C as catalyst (2:5 DMF/EtOAc, r.t.) afterpurification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 6.17-6.79 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 7.94 (m, J=8.85, 5.19, 2H), 7.87 (dd,J=8.09, 1.98, 1H), 7.74 (d, J=1.83, 1H), 7.50 (d, J=7.93, 1H), 7.44 (s,1H), 7.38 (s, 1H), 7.17 (m, 1H), 7.29 (s, 1H), 7.29-7.25 (overlapping m,5H), 2.92 (s, 3H), 2.24 (s, 3H), 1.35 (m, 4H). LC/MS were performed byusing Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18,3.0×50 mm; (ES+) m/z (M+H)⁺=534.26, HPLC R_(t)=1.563 min. AnalyticalHPLC were performed by using Shimadzu-VP instrument with UV detection at220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95%H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=11.58 min; Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=4.96 min (Start % B=50). Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=10, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl, Rt=15.09min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-(methylsulfonamido)benzofuran-3-carboxamide

To a mixture of6-amino-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide(53.3 mg, 0.100 mmol) (crude) in C1CH₂CH₂Cl (1 ml) at r.t. under N₂ wasadded pyridine (0.024 mL, 0.300 mmol). The mixture was then added asolution of methanesulfonyl chloride (22.88 mg, 0.200 mmol) inC1CH₂CH₂Cl (0.3 ml), and stirred for about 22 hours. The mixture wasdiluted with MeOH and purified by Shimadzu-VP preparative reverse phaseHPLC using the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.75-7.37 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, J=8.85, 5.19,2H), 7.85 (dd, J=8.09, 1.98, 1H), 7.79 (s, 1H), 7.75 (d, J=1.53, 1H),7.51 (s, 1H), 7.47 (d, J=7.93, 1H), 7.17 (m, 1H), 7.30-7.26 (overlappingm, 5H), 7.29 (s, 1H), 2.93 (s, 3H), 2.88 (s, 3H), 2.23 (s, 3H), 1.35(appeared as d, 4H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=612.34, HPLC R_(t)=1.583 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=7.48 min; Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=6.24 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl, Rt=11.46 min.

2-(4-Fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamidewas prepared from the alkylation of2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-phenylcyclopropylcarbamoyl)phenyl)-6-(methylsulfonamido)benzofuran-3-carboxamideusing (2-bromoethoxy)(tert-butyl)dimethylsilane (K₂CO₃, DMF 55° C.)followed by deprotection using HCl in 1,4-dioxane at r.t. Purificationwas preformed by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, Fraction Collection: 6.32-6.81 min. (UV detection at 220nm). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Xterra MS 7 um, C18, 3.0×50 mm; (ES+) m/z (M+H)⁺=656.06, HPLCR_(t)=1.563 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=6.05 min; Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=5.38 min.Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, SolventB=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradienttime=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: XbridgePhenyl 3.5 um, 4.6×150 mm, R_(t)=11.42 min.

5-(2-Fluoro-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide

Purification was preformed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=30, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 8.06-8.30 min. (UVdetection at 220 nm). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Xterra MS 7 um, C18, 3.0×50 mm;(ES+) m/z (M+H)⁺=660.50, HPLC R_(t)=1.530 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=5.68 min; Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=5.18 min.

General Procedure.

To a Biotage microwave vial (2-5 mL) was added either5-(4-chloro-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(0.075 mmol, 1 eq.) or4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-(isobutylcarbamoyl)phenyltrifluoromethane sulfonate (0.075 mmol, 1 eq.) in dry 1,4-Dioxane (1 mL)along with the desired boronic acid (0.150 mmol, 2 eq.), potassiumphosphate, tribasic (0.300 mmol, 52.3 mg) in water (0.2 mL),dicyclohexyl(2′,6′-dimethoxybiphenyl-3-yl)phosphine (S-Phos) (6.16 mg,0.015 mmol), and finally palladium (II) acetate (3.37 mg, 0.015 mmol) in1,4-dioxane (0.5 mL). The vial was flushed with nitrogen then capped andplaced into the Biotage microwave for 10 minutes at 150° C. The solventwas removed in a Thermo/Savant SpeedVac and the crude products weredissolved in DMF (1.8 mL) and purified by preparative HPLC using aShimadzu prepHPLC employing acetonitrile/water/0.1% TFA where solvent Awas 10% acetonitrile/90% H₂O/0.1% trifluoroacetic acid and solvent B was10% H₂O/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire5 μm C18 30×100 mm column at a gradient of 30-100% B and a flow rate of40 mL/min. over 8 minutes with a 10 minute hold. The tubes with desiredproduct were evaporated overnight in a Thermo/Savant Speedvac. The LC/MSdata was obtained on a Shimadzu analytical LC/Micromass Platform LC(ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% TFA/10% HPLC grade water), (A=90% HPLC gradewater/0.1% TFA/10% HPLC grade acetonitrile), in 3 minutes with a 1minute hold at a rate of 4 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 20-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Phenomenex Gemini C18 3 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of20-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. Rt represents the LC retention time in minutes. All NMRspectra were recorded at room temperature using deuterated NMR solvents.

5-(4-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-(isobutylcarbamoyl)phenyl)-N-methylpicolinamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.75 (d, J=7 Hz, 6H), 1.63-1.71 (m, 1H),2.93 (d, J=5 Hz, 6H), 3.00 (t, J=6 Hz, 2H), 7.23 (t, J=9 Hz, 2H), 7.37(t, J=6 Hz, 1H), 7.44-7.51 (m, 1H), 7.53 (d, J=8 Hz, 1H), 7.60-7.66 (m,1H), 7.67-7.73 (m, 1H), 7.80-7.88 (m, 2H), 7.98 (dd, J=8, 2 Hz, 1H),8.05 (s, 1H), 8.08-8.18 (m, 3H), 8.30 (d, J=5 Hz, 1H), 8.66 (d, J=2 Hz,1H). LCMS Rt 2.125 min., m/z 579.32 (M+H), HPLC Rt 8.594 min. (SunfireC18), 98.7% purity and 11.276 min. (Gemini C18), 100% purity.

4-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-N2-isobutylbiphenyl-2,4′-dicarboxamide

¹H NMR (400 MHz, DMF-d7) δ ppm 0.81 (d, J=6.78 Hz, 6H), 1.71-1.82 (m,1H), 3.00 (d, J=4.77 Hz, 3H), 3.06 (t, J=6.40 Hz, 2H), 7.42-7.48 (m,2H), 7.57 (d, J=8.28 Hz, 1H), 7.62 (m, 2H), 7.78 (d, J=8.28 Hz, 1H),7.84 (m, 2H), 7.94 (d, J=8.03 Hz, 1H), 8.00 (d, J=8.28 Hz, 2H),8.06-8.08 (m, 1H), 8.10-8.14 (m, 2H), 8.20 (t, J=5.77 Hz, 1H), 8.40 (d,J=4.52 Hz, 1H). LCMS Rt 2.020 min, m/z 564.25 (M+H). HPLC Rt 8.224 min.(Sunfire C18), 98.2% purity and 11.098 min. (Gemini C18), 98.3% purity.

5-(4-(5-Cyanopyridin-3-yl)-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.82 (d, J=6.78 Hz, 6H), 1.74-1.80 (m,1H), 2.93 (d, J=4.52 Hz, 3H), 3.01-3.11 (m, 2H), 7.18-7.30 (m, 2H),7.42-7.51 (m, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.56-7.61 (m, 1 H),7.62-7.67 (m, 1H), 7.68-7.75 (m, 1H), 7.83-7.92 (m, 2H), 8.04-8.15 (m, 3H), 8.20 (t, J=2.13 Hz, 1H), 8.85 (dd, J=13.93, 2.13 Hz, 2H). LCMS Rt2.278 min, m/z 547.23 (M+H). HPLC Rt 9.246 min. (Sunfire C18), 96.0%purity and 11.343 min. (Gemini C18), 98.6% purity.

An alternative approach to the coupling. To a small sized microwave vialwas added5-(4-chloro-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(47.9 mg, 0.1 mmol), BuOH (2 mL), boronic acid/ester (0.150 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (19.07 mg,0.040 mmol), potassium phosphate, tribasic (85 mg, 0.400 mmol) andfinally Tris(dibenzylideneacetone)dipalladium(0) (18.31 mg, 0.020 mmol).The vial was capped and subjected to microwave heating (130° C.) for 12minutes. Butanol was removed under a stream of nitrogen and the crudeproducts were dissolved in DMF (1.8 mL) and purified by preparative HPLCemploying a Dionex PrepHPLC system equipped with an ELS (EvaporativeLight Scattering) detector. A Waters Xbridge 19×200 mm 5 um C18 columnwas used with acetonitrile/HPLC grade water/10 mM ammonium acetate wheresolvent A was HPLC grade water with 10 mM ammonium acetate and solvent Bwas 100% acetonitrile at a gradient of 30-95% B in 30 minutes with aflow rate of 25 mL/minute. LCMS was run using a Waters ZQ with ESCi massspectrometer with a Supelco Ascentis Express 3 μm C18 4.5×50 mm columnemploying acetonitrile/HPLC grade water/10 mM ammonium acetate wheresolvent A was 5% acetonitrile, 95% HPLC grade water with 10 mM ammoniumacetate and solvent B was 95% acetonitrile, 5% HPLC grade water with 10mM ammonium acetate at a gradient of 0-100% B in 8 minutes with a 1minute hold at 2 mL/minute.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(2-methylpyridin-3-yl)phenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 535.90 (M+H), Rt 4.89 min., 100% purity.

5-(4-(5-Aminopyridin-3-yl)-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 536.96 (M+H), Rt 4.37 min., 100% purity.

5-(4-(2,4-Dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 554.94 (M+H), Rt 3.88 min., 100% purity.

5-(4-(2-Aminopyridin-4-yl)-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 536.97 (M+H), Rt 4.55 min., 100% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(5-methoxypyridin-3-yl)phenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 551.96 (M+H), Rt 4.97 min., 89% purity.

5-(4-(2-Aminopyrimidin-5-yl)-3-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 537.97 (M+H), Rt 4.23 min., 96% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(5-methylpyridin-3-yl)phenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 535.95 (M+H), Rt 4.99 min., 100% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(thiophen-3-yl)phenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 526.96 (M+H), Rt 5.83 min., 74% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-(pyrimidin-5-yl)phenyl)-N-methylbenzofuran-3-carboxamide

Purification by using a Shimadzu preparative HPLC employingCH₃CN/water/TFA where solvent A was 10% acetonitrile/90% H2O/0.1%trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1%trifluoroacetic acid with a Waters Sunfire 5u C18 30×100 mm column at agradient of 30-100% B and a flow rate of 40 mL/min. over 10 minutes witha 10 minute hold. Post purification LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column,with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% TFA/10%HPLC grade water), (A=90% HPLC grade water/0.1% TFA/10% HPLC gradeacetonitrile), in 3 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a PhenomenexGemini C18 3 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.76 (d, J=6.78 Hz, 6H), 1.61-1.74 (m, 1H), 2.87 (d,J=4.52 Hz, 3H), 2.96 (t, J=6.27 Hz, 2H), 7.39 (t, J=8.91 Hz, 2H), 7.64(d, J=8.03 Hz, 1H), 7.77-7.87 (m, 3H), 7.91-8.07 (m, 4H), 8.47-8.60 (m,2H), 8.81 (s, 2H), 9.16 (s, 1H). LCMS m/z 523.22 (M+H), Rt 2.052 min.HPLC Rt 8.908 min. (Sunfire C18), 96.0% purity and 11.353 min. (GeminiC18), 98.6% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-methoxyethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

To a small microwave vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(33 mg, 0.072 mmol), tetrahydrofuran (2 mL), triphenylphosphine (37.6mg, 0.143 mmol), 2-methoxyethanol (0.011 mL, 0.139 mmol), anddi-tert-butyl azodicarboxylate (33.0 mg, 0.143 mmol). The vial wascrimped and heated to 100° C. for 10 minutes. After returning to roomtemperature tetrahydrofuran was removed under a stream of nitrogen. Thecrude product was taken up in 2 mL of acetonitrile and purified using aShimadzu preparative HPLC employing acetonitrile/water/0.1% TFA wheresolvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid witha Waters Sunfire 5 μm C18 30×100 mm column at a gradient of 40-100% Band a flow rate of 40 mL/min. over 8 minutes with a 10 minute hold. Thedesired material was concentrated to dryness. The resulting white solid(41% yield) was placed under high vacuum prior to final analysis. TheLC/MS data was obtained on a Shimadzu analytical LC/Micromass PlatformLC (ESI+) at 220 nm using the following set of conditions: WatersSunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90%HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water),(A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 3 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. The NMR spectrumwas recorded at room temperature using a Bruker DRX400 spectrometer.Chemical shifts were reported in ppm relative to the deuterated solventused. Coupling constants were reported in hertz. Peak multiplicity wasreported using the following abbreviations: s (singlet), d (doublet), dd(doublet of doublets), t (triplet), m (multiplet), br (broad). ¹H NMR(400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.53 Hz, 6H), 1.35-1.40 (m, 3H),1.96-2.08 (m, 1H), 2.97-3.10 (m, 3H), 3.24-3.32 (m, 2H), 3.73-3.82 (m,2H), 4.25-4.34 (m, 2H), 7.24 (d, J=8.53 Hz, 1H), 7.29-7.38 (m, 2H),7.63-7.72 (m, 2H), 7.91 (dd, J=8.53, 2.26 Hz, 1H), 7.94-7.99 (m, 2H),8.00-8.09 (m, 2H), 8.48 (br. s., 1H). LCMS m/z 519.25 (M+H), Rt 2.292min. HPLC (Sunfire C18) Rt 10.054 min, 96% purity and (XBridge PhenylC18) Rt 11.846 min., 97% purity.

Additional examples of ether linked compounds are shown below. Thecompounds were synthesized in the same manner as above. The solvent(tetrahydrofuran) was removed under a stream of nitrogen and the crudeproducts were dissolved in DMF (1.8 mL) and purified by preparative HPLCemploying a Dionex PrepHPLC system equipped with an ELS (EvaporativeLight Scattering) detector. A Supelco Ascentis 5 μm C18 21.2×250 mmcolumn was used with acetonitrile/HPLC grade water/10 mM ammoniumacetate where solvent A was 99.9% HPLC grade water with 10 mM ammoniumacetate and solvent B was 100% acetonitrile at a gradient of 30-95% B in20 minutes with a 2.5 minute hold at 20 mL/minute. LCMS was run using aWaters ZQ with ESCi mass spectrometer with a Supelco Ascentis Express 3μm C18 4.5×50 mm column employing acetonitrile/HPLC grade water/10 mMammonium acetate where solvent A was 5% acetonitrile, 95% HPLC gradewater with 10 mM ammonium acetate and solvent B was 95% acetonitrile, 5%HPLC grade water with 10 mM ammonium acetate at a gradient of 0-100% Bin 8 minutes with a 1 minute hold at 2 mL/minute. The NMR spectra wererecorded at room temperature using a Varian 600 MHz flow spectrometer.Chemical shifts were reported in ppm relative to the 75% DMSO-d6/25%CDCl₃ (v/v) solvent used.

2-(4-Fluorophenyl)-5-(2-(4-hydroxyphenethoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.88 (d, J=7.03 Hz, 6H), 1.85(ddd, J=13.33, 6.59, 6.44 Hz, 1H), 2.77-2.94 (m, 5H), 3.08 (t, J=6.15Hz, 2H), 4.20 (t, J=6.44 Hz, 2H), 6.59-6.68 (m, 2H), 6.98 (d, J=8.20 Hz,2H), 7.13 (d, J=8.79 Hz, 1H), 7.32 (t, J=8.79 Hz, 1H), 7.41 (d, J=8.79Hz, 1H), 7.59 (d, J=8.20 Hz, 1H), 7.75 (s, 1H), 7.81-7.91 (m, 2H), 8.00(dd, J=8.20, 5.27 Hz, 1H), 8.33 (t, J=5.57 Hz, 1H), 8.39 (d, J=4.10 Hz,1H). LCMS m/z 581.48 (M+H), Rt 5.30 min., 90% purity.

5-(2-(3-(1H-pyrrol-1-yl)propoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.80-1.91(m, 1H), 2.07 (m, 2H), 2.79 (d, J=4.10 Hz, 3H), 3.09 (t, J=6.44 Hz, 2H),3.90-4.01 (m, 4H), 5.94 (s, 2 H), 6.61 (s, 2H), 7.08 (d, J=8.79 Hz, 1H),7.32 (t, J=8.50 Hz, 2H), 7.58 (d, J=8.20 Hz, 1H), 7.70 (d, J=8.79 Hz,1H), 7.79-7.87 (m, 2H), 7.92 (s, 1H), 7.97 (dd, J=8.50, 5.57 Hz, 2H),8.32-8.42 (m, 2H). LCMS m/z 568.47 (M+H), Rt 5.98 min., 100% purity.

2-(4-Fluorophenyl)-5-(2-(4-chlorophenethoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.88 (d, J=7.03 Hz, 6H), 1.80-1.90(m, 1H), 2.84 (d, J=4.69 Hz, 3H), 2.96 (t, J=6.15 Hz, 2H), 3.08 (t,J=6.15 Hz, 2H), 4.26 (t, J=6.44 Hz, 2H), 7.14 (d, J=8.79 Hz, 1H), 7.19(d, J=8.20 Hz, 2H), 7.23-7.27 (m, 2H), 7.29-7.39 (m, 3H), 7.58 (d,J=8.79 Hz, 1H), 7.73 (s, 1H), 7.83-7.89 (m, 2H), 8.00 (dd, J=8.50, 5.57Hz, 2H), 8.33 (t, J=5.27 Hz, 1H), 8.38 (d, J=4.10 Hz, 1H). LCMS m/z599.47 (M+H), Rt 6.52 min., 92% purity.

2-(4-Fluorophenyl)-5-(2-(6-(hydroxymethyl)pyridin-2-yl)methoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.79-1.91(m, 1H), 2.82 (d, J=4.10 Hz, 3H), 3.09 (t, J=6.44 Hz, 2H), 4.56 (s, 2H),5.23 (s, 2H), 7.24 (t, J=9.37 Hz, 2H), 7.32 (t, J=8.79 Hz, 2H), 7.37 (d,J=8.20 Hz, 1H), 7.60-7.65 (m, 1 H), 7.66-7.70 (m, 1H), 7.75 (t, J=7.62Hz, 1H), 7.84-7.90 (m, 2H), 7.93 (s, 1H), 7.96-8.03 (m, 2H), 8.36 (t,J=5.57 Hz, 1H), 8.40 (d, 1H). LCMS m/z 582.48 (M+H), Rt 4.57 min., 93%purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(3-morpholinopropoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=7.03 Hz, 6H), 1.77-1.91(m, 3H), 2.23-2.43 (m, 6H), 2.84 (d, J=4.10 Hz, 3H), 3.08 (t, J=6.44 Hz,2H), 3.53 (br. s., 4H), 4.09 (t, J=5.86 Hz, 2H), 7.14 (d, J=8.20 Hz,1H), 7.32 (t, J=8.79 Hz, 2H), 7.53 (d, J=9.37 Hz, 1H), 7.65 (d, J=8.79Hz, 1H), 7.78 (s, 1H), 7.84-7.92 (m, 2H), 7.98 (dd, J=7.91, 5.57 Hz,2H), 8.31-8.43 (m, 2H). LCMS m/z 588.40 (M+H), Rt 4.05 min., 98.7%purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-morpholinoethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H, 1.79-1.91(m, 1H), 2.38 (br. s., 4H), 2.64 (t, J=5.57 Hz, 2H), 2.84 (d, J=4.10 Hz,3H), 3.08 (t, J=6.15 Hz, 2H), 3.52 (t, J=4.39 Hz, 4H), 4.17 (t, J=5.57Hz, 2H), 7.16 (d, J=8.79 Hz, 1H), 7.32 (t, J=8.79 Hz, 2H), 7.56-7.61 (m,1H), 7.61-7.66 (m, 1H), 7.75 (s, 1H), 7.83-7.91 (m, 2H), 7.98 (dd,J=8.20, 5.86 Hz, 2H), 8.35 (t, J=5.27 Hz, 1H), 8.38 (d, 1H). LCMS m/z574.35 (M+H), Rt 3.95 min., 100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(pyridin-2-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=7.03 Hz, 6H), 1.82-1.91(m, 1H), 2.79-2.86 (m, 3H), 3.09 (t, J=6.44 Hz, 2H), 5.27 (s, 2H),7.22-7.30 (m, 2H), 7.33 (t, J=8.50 Hz, 2H), 7.40 (d, J=7.62 Hz, 1H),7.62 (d, J=8.79 Hz, 1H), 7.66-7.71 (m, 1H), 7.76 (t, J=7.62 Hz, 1H),7.84-7.91 (m, 2H), 7.94 (s, 1H), 7.99 (dd, J=8.50, 5.57 Hz, 2H),8.35-8.44 (m, 2 H), 8.53 (d, J=4.69 Hz, 1H). LCMS m/z 552.29 (M+H), Rt4.29 min., 100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.64 (br.s., 4H), 1.80-1.91 (m, 1H), 2.47 (br. s., 4H), 2.75-2.82 (m, 2H), 2.84(d, J=4.10 Hz, 3H), 3.08 (t, J=6.44 Hz, 2H), 4.16 (t, J=5.27 Hz, 2H),7.16 (d, 1H), 7.32 (t, J=8.79 Hz, 2H), 7.56-7.61 (m, 1H), 7.61-7.66 (m,1H), 7.78 (s, 1H), 7.86 (d, J=8.20 Hz, 1H), 7.89 (s, 1H), 7.98 (dd,J=8.20, 5.27 Hz, 2H), 8.31-8.43 (m, 2H). LCMS m/z 558.37 (M+H), Rt 3.52min., 100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-(piperidin-1-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.32-1.38(m, 2H), 1.38-1.43 (m, 2H), 1.44-1.52 (m, 2H), 1.79-1.93 (m, 1H),2.32-2.45 (m, 4H), 2.57-2.68 (m, 2H), 2.84 (d, J=4.10 Hz, 3H), 3.08 (t,J=6.15 Hz, 2H), 4.10-4.20 (m, 2H), 7.16 (d, J=8.79 Hz, 1H), 7.32 (t,J=8.79 Hz, 2H), 7.61 (q, J=8.79 Hz, 2H), 7.76 (s, 1H), 7.86 (d, J=8.20Hz, 1H), 7.89 (s, 1H), 7.98 (dd, J=8.20, 5.86 Hz, 2H), 8.31-8.44 (m,2H). LCMS m/z 572.37 (M+H), Rt 3.89 min., 95.4% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-(pyridin-2-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.88 (d, J=6.44 Hz, 6H), 1.79-1.91(m, 1H), 2.84 (d, J=4.69 Hz, 3H), 3.08 (t, J=6.15 Hz, 2H), 3.21 (t,J=6.15 Hz, 2H), 4.47 (t, J=6.15 Hz, 2H), 7.20 (dd, J=19.92, 8.20 Hz,2H), 7.29-7.41 (m, 4H), 7.50 (d, J=8.79 Hz, 1H), 7.67 (s, 1H), 7.79-7.91(m, 3H), 8.00 (dd, J=8.50, 5.57 Hz, 2H), 8.34 (t, J=5.57 Hz, 1H), 8.45(d, J=4.10 Hz, 1H), 8.51 (d, J=4.69 Hz, 1H). LCMS m/z 566.34 (M+H), Rt4.32 min., 100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-((2-methyl-1H-imidazol-4-yl)methoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.85 (dd,J=12.01, 6.74 Hz, 1H), 2.14-2.38 (m, 3H), 2.81-2.88 (m, 3H), 3.04-3.12(m, 2H), 5.00 (s, 1H), 6.91-7.03 (m, 1H), 7.32 (t, J=9.08 Hz, 2H),7.50-7.68 (m, 2H), 7.70 (d, J=6.44 Hz, 1H), 7.79 (d, J=4.10 Hz, 2H),7.86 (d, J=11.72 Hz, 1H), 7.94 (s, 1H), 7.96-8.04 (m, 1H), 8.34 (t,J=5.57 Hz, 1H), 8.40 (d, J=4.69 Hz, 1H). LCMS m/z 555.34 (M+H), Rt 3.57min., 93.3% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.90 (d, J=7.03 Hz, 6H), 1.82-1.92(m, 1H), 2.79 (d, J=4.69 Hz, 3H), 3.09 (t, J=6.15 Hz, 2H), 5.39 (s, 2H),7.27 (d, J=8.79 Hz, 1H), 7.34 (t, J=8.50 Hz, 2H), 7.62 (t, J=8.50 Hz,2H), 7.71 (d, J=8.20 Hz, 1H), 7.89 (d, J=8.20 Hz, 1H), 7.92 (s, 1H),7.95-8.02 (m, 3H), 8.16 (d, J=8.20 Hz, 1H), 8.39 (t, J=5.57 Hz, 1H),8.44 (d, J=4.69 Hz, 1H), 8.90 (s, 1H). LCMS m/z 620.32 (M+H), Rt 5.09min., 97.9% purity.

5-(2-((1H-imidazol-4-yl)methoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LCMS m/z 541.29 (M+H), Rt 3.51 min., 100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-((1-methyl-1H-imidazol-4-yl)methoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.88 (d, J=6.44 Hz, 6H), 1.83 (dt,J=13.48, 6.74 Hz, 1H), 2.84 (d, J=4.69 Hz, 3H), 3.06 (t, J=6.44 Hz, 2H),3.63 (s, 3H), 3.88 (s, 2H), 7.00 (s, 1H), 7.32 (t, J=8.79 Hz, 2H), 7.55(d, J=8.20 Hz, 1H), 7.63-7.70 (m, 3H), 7.74 (d, J=14.65 Hz, 2H), 7.94(s, 1H), 7.99 (dd, J=8.20, 5.27 Hz, 2H), 8.23 (s, 1H), 8.39 (d, J=4.10Hz, 1H). LCMS m/z 555.35 (M+H), Rt 4.11 min., 100% purity.

2-(4-Fluorophenyl)-5-(2-(hex-2-ynyloxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.83-0.97 (m, 9H), 1.36-1.48 (m,2H), 1.82-1.90 (m, 1H), 2.16 (t, J=6.74 Hz, 2 H), 2.84 (d, J=4.69 Hz,3H), 3.09 (t, J=6.44 Hz, 2H), 4.82 (br. s., 2H), 7.23 (d, J=8.20 Hz,1H), 7.29-7.33 (m, 2H), 7.51 (d, J=8.79 Hz, 1H), 7.65 (d, J=8.20 Hz,1H), 7.72 (s, 1H), 7.84-7.91 (m, 2H), 7.99 (dd, J=8.20, 5.27 Hz, 2H),8.36 (t, J=5.57 Hz, 1H), 8.40 (d, J=4.10 Hz, 1H). LCMS m/z 541.35 (M+H),Rt 5.20 min., 95.3% purity.

5-(2-(2,2-Difluoroethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.86 (dt,J=13.48, 6.74 Hz, 1H), 2.84 (d, J=4.10 Hz, 3H), 3.09 (t, J=6.44 Hz, 2H),4.39 (td, J=14.35, 2.93 Hz, 2H), 6.15-6.40 (m, 1H), 7.23 (d, J=8.79 Hz,1H), 7.32 (t, J=8.79 Hz, 2H), 7.56 (d, J=8.79 Hz, 1H), 7.66 (d, J=8.20Hz, 1H), 7.79 (s, 1H), 7.89 (d, J=8.79 Hz, 1H), 7.93 (s, 1H), 7.99 (dd,J=8.20, 5.27 Hz, 2H), 8.35-8.44 (m, 2H). LCMS m/z 525.27 (M+H), Rt 4.44min., 97.4% purity.

5-(2-((2-Bromopyridin-4-yl)methoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (600 MHz, DMSO-d6/CDCl₃) δ ppm 0.89 (d, J=6.44 Hz, 6H), 1.81-1.91(m, 1H), 2.82 (d, J=4.69 Hz, 3H), 3.09 (t, J=6.15 Hz, 2H), 5.27 (s, 2H),7.21 (d, J=8.79 Hz, 1H), 7.33 (t, J=8.50 Hz, 2H), 7.37 (d, J=4.69 Hz,1H), 7.54 (s, 1H), 7.61 (d, J=8.79 Hz, 1H), 7.70 (d, J=8.79 Hz, 1H),7.83 (s, 1H), 7.89 (d, J=8.79 Hz, 1H), 7.94 (s, 1H), 7.99 (dd, J=8.20,5.27 Hz, 2H), 8.32 (d, J=5.27 Hz, 1H), 8.38 (d, J=4.69 Hz, 2H). LCMS m/z630.26 (M+H), Rt 4.71 min., 98.4% purity.

5-(2-(2-(Dibenzylamino)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Post purification LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of4 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mmcolumn employing water/methanol/10 mM ammonium bicarbonate with agradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammoniumbicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammoniumbicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute holdat a rate of 1 mL/minute. The NMR spectrum was recorded at roomtemperature using a Bruker DRX400 spectrometer. ¹H NMR (400 MHz, CD₃OD)δ ppm 0.96 (d, J=6.53 Hz, 6 H), 1.83-2.07 (m, 1H), 2.81 (t, J=5.40 Hz,2H), 2.90 (s, 3H), 3.19 (d, J=7.03 Hz, 2H), 3.53 (s, 4H), 4.10 (t,J=5.40 Hz, 2H), 6.99 (d, J=8.53 Hz, 1H), 7.14 (dd, J=5.52, 3.01 Hz, 2H),7.17-7.23 (m, 8H), 7.23-7.29 (m, 2H), 7.41-7.47 (m, 1H), 7.48-7.55 (m,1H), 7.75-7.82 (m, 2H), 7.84 (d, J=2.26 Hz, 1H), 7.92 (dd, J=8.66, 5.40Hz, 2H). LCMS m/z 684.40 (M+H), Rt=1.897 min. HPLC Rt 14.159 min.(XBridge Phenyl C18), 100% purity.

5-(2-(3-Aminocyclopentyloxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Post purification LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+/−) at 220 nm using the following set ofconditions: Luna 10 μm C18, 3.0×50 mm column, with a gradient of 0-100%B (B=95% HPLC grade acetonitrile/10 mM ammonium acetate/5% HPLC gradewater), (A=95% HPLC grade water/10 mM ammonium acetate/5% HPLC gradeacetonitrile), in 4 minutes with a 1 minute hold at a rate of 5mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Gemini C18 3.0 μm 4.6×150 mm column employingwater/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B(B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC gradewater), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grademethanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.The NMR spectrum was recorded at room temperature using a Bruker DRX400spectrometer. ¹HNMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.78 Hz, 6H),1.77-1.97 (m, 3H), 2.04-2.19 (m, 2H), 2.19-2.32 (m, 2H), 2.90 (d, J=4.52Hz, 3H), 3.17 (t, J=6.40 Hz, 2H), 3.69-3.82 (m, 2H), 7.04 (d, J=8.53 Hz,1H), 7.21 (t, J=8.78 Hz, 2H), 7.41-7.50 (m, 1H), 7.50-7.56 (m, 1H),7.60-7.72 (m, 2H), 7.81 (dd, J=8.66, 2.13 Hz, 1H), 7.85 (d, J=1.25 Hz,1H), 7.90 (d, J=2.01 Hz, 1H), 7.99-8.10 (m, 2H), 8.42 (br. s., 2H). LCMSRt 1.937 min., m/z 542.34 (M−H) and m/z 544.29 (M+H). HPLC Rt 6.870 min.(Sunfire C18), 99.1% purity and 11.133 min. (Gemini C18), 98.9% purity.

An alternative synthesis to these ether linked analogs was carried outusing phenol template in DMF with alkyl bromides and DBU. To a 2 dramvial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(46.0 mg, 0.1 mmol), DMF (2 mL), 4.0 equivalents of DBU,1,8-Diazabicyclo[5.4.0]undec-7-ene (0.4 mmol) and 3.0 equivalents (0.3mmol) of alkyl bromide. The vials were sealed and shaken at 75° C. in adry bath. Upon reaction completion the crude products were concentrated,diluted with 2 mL of acetonitrile and purified using a Shimadzupreparative HPLC employing acetonitrile/water/0.1% TFA where solvent Awas 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent Bwas 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a WatersSunfire 5 μm C18 4.6×100 mm column at a gradient of 30-100% B and a flowrate of 40 mL/min. over 8 minutes with a 10 minute hold. The desiredproducts were evaporated to dryness in a Savant Speedvac overnightobtaining 25-60% yield of the desired ethers as powders. The NMRspectrum was recorded at room temperature using a Bruker DRX400spectrometer. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of4 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute.

5-(2-(2-Amino-2-oxoethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.86-1.02 (m, 6H), 1.81-1.99 (m, 1H),2.91 (d, J=4.77 Hz, 3H), 3.06-3.29 (m, 2H), 4.46 (s, 2H), 6.43 (br. s.,1H), 6.69 (br. s., 1H), 7.08 (d, J=8.78 Hz, 1H), 7.16-7.27 (m, 2H), 7.53(br. s., 1H), 7.56-7.62 (m, 2H), 7.86 (dd, J=8.53, 2.26 Hz, 1H), 7.93(d, J=2.26 Hz, 1H), 7.97 (s, 1H), 8.09-8.19 (m, 2H). LCMS m/z 518.36(M+H), Rt 1.880 min. HPLC (Sunfire C18) Rt 8.209 min, 100% purity and(XBridge Phenyl C18) Rt 11.254 min., 99.8% purity.

5-(2-(2-(1H-indol-3-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 0.92-1.04 (m, 6H), 1.87-2.03 (m, 1H), 2.95(s, 3H), 3.15-3.24 (m, 4H), 4.37 (t, J=6.71 Hz, 2H), 6.94 (t, J=7.48 Hz,1H), 6.98 (s, 1H), 7.07 (t, J=7.63 Hz, 1H), 7.18 (d, J=8.55 Hz, 1H),7.24-7.36 (m, 3H), 7.44-7.50 (m, 2H), 7.51-7.56 (m, 1H), 7.84 (td,J=4.27, 2.44 Hz, 2H), 7.88 (d, J=2.14 Hz, 1H), 7.94-8.03 (m, 2H). LCMSm/z 604.31 (M+H), Rt 2.621 min. HPLC Rt 11.054 min. (Sunfire C18), 98.1%purity and 12.561 min. (XBridge Phenyl C18), 97.8% purity.

5-(2-(2-(1H-indol-3-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 0.87-1.03 (m, 6H), 1.83-2.00 (m, 1H), 2.17(dd, J=9.77, 5.49 Hz, 2H), 2.81-2.90 (s, 3 H), 2.90-3.00 (s, 3H),3.12-3.25 (m, 4H), 3.42 (br. s., 8H), 4.21 (t, J=5.65 Hz, 2 H), 7.17 (d,J=8.85 Hz, 1H), 7.22-7.33 (m, 2H), 7.53 (dd, J=8.55, 1.83 Hz, 1H), 7.65(d, J=8.24 Hz, 1H), 7.86 (td, J=8.47, 2.29 Hz, 3H), 7.89-7.96 (m, 2H).LCMS m/z 601.36 (M+H), Rt 1.375 min. HPLC Rt 6.010 min. (Sunfire C18),99.3% purity and 11.793 min. (XBridge Phenyl C18), 98.4% purity.

5-(2-(2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 0.89-1.01 (m, 6H), 1.86-1.98 (m, 1H), 2.02(s, 6H), 2.90 (t, J=5.95 Hz, 2H), 2.95 (s, 3H), 3.14-3.22 (m, 2H), 4.24(t, J=5.95 Hz, 2H), 7.18 (d, J=8.55 Hz, 1H), 7.24-7.33 (m, 2H), 7.37(dd, J=8.39, 1.68 Hz, 1H), 7.59 (d, J=8.55 Hz, 1H), 7.68 (d, J=1.83 Hz,1H), 7.80 (d, J=2.44 Hz, 1H), 7.85 (dd, J=8.70, 2.29 Hz, 1H), 7.93-8.02(m, 2H). LCMS m/z 583.32 (M+H), Rt 1.698 min. HPLC Rt 7.270 min.(Sunfire C18), 92.6% purity and 11.994 min. (XBridge Phenyl C18), 92.0%purity.

2-(4-Fluorophenyl)-5-(2-(2-hydroxybutoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 0.93-1.15 (m, 9H), 1.45-1.61 (m, 1H),1.61-1.77 (m, 1H), 2.01 (dt, J=13.55, 6.78 Hz, 1H), 3.03 (s, 3H), 3.27(d, J=7.03 Hz, 2H), 3.81-3.90 (m, 1H), 4.10 (d, J=5.02 Hz, 2H), 7.24 (d,J=8.78 Hz, 1H), 7.28-7.38 (m, 2H), 7.62-7.72 (m, 2H), 7.91 (dd, J=8.53,2.26 Hz, 1H), 7.96 (d, J=2.01 Hz, 2H), 8.00-8.08 (m, 2H). LCMS m/z533.30 (M+H), Rt 2.238 min. HPLC Rt 11.383 min. (Sunfire C18), 95.4%purity and 11.896 min. (XBridge Phenyl C18), 98.5% purity.

2-(4-Fluorophenyl)-5-(2-(2-hydroxypropoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.53 Hz, 6H), 1.27 (d, J=6.27Hz, 3H), 1.93-2.08 (m, 1H), 3.03 (s, 3H), 3.27 (d, J=7.03 Hz, 2H),3.97-4.15 (m, 3H), 7.23 (d, J=8.53 Hz, 1H), 7.32 (t, J=8.91 Hz, 2H),7.67 (d, J=1.00 Hz, 2H), 7.86-7.93 (m, 1H), 7.96 (d, J=2.26 Hz, 2H),8.03 (dd, J=9.04, 5.27 Hz, 2H). LCMS m/z 519.28 (M+H), Rt 2.100 min.HPLC Rt 9.279 min. (Sunfire C18), 98.4% purity and 11.674 min. (XBridgePhenyl C18), 98.8% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-(piperidin-2-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 0.92-1.04 (m, 6H), 1.32-1.48 (m, 2H), 1.59(d, J=14.34 Hz, 1H), 1.78 (br. s., 2H), 1.88-2.06 (m, 3H), 2.11-2.25 (m,1H), 2.85 (m, 1H), 2.96 (s, 3 H), 3.11-3.27 (m, 4H), 4.17-4.37 (m, 2H),7.23 (d, J=8.85 Hz, 1H), 7.26-7.36 (m, 2H), 7.55 (dd, J=8.55, 1.83 Hz,1H), 7.70 (d, J=8.55 Hz, 1H), 7.83-8.01 (m, 5 H). LCMS m/z 572.33 (M+H),Rt 1.663 min. HPLC Rt 7.638 min. (Sunfire C18), 98.8% purity and 12.003min. (XBridge Phenyl C18), 97.3% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(pyridin-4-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, CD₃OD) δ ppm 0.98 (d, J=6.71 Hz, 6H), 1.83-2.07 (m,1H), 2.92 (s, 3H), 3.22 (d, J=7.02 Hz, 2H), 5.54 (s, 2H), 7.19-7.39 (m,3H), 7.62 (dd, J=8.55, 1.53 Hz, 1H), 7.65-7.72 (m, 1H), 7.88-7.99 (m,5H), 8.01 (d, J=6.41 Hz, 2H), 8.79 (d, J=6.71 Hz, 2H). LCMS m/z 552.28(M+H), Rt 1.600 min. HPLC Rt 6.831 min. (Sunfire C18), 99.5% purity and11.871 min. (XBridge Phenyl C18), 99.3% purity.

tert-Butyl2-(2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-(isobutylcarbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate

¹H NMR (400 MHz, CD₃OD) δ ppm 1.04 (d, J=6.53 Hz, 6H), 1.48 (s, 9H),1.65-1.84 (m, 2H), 1.91-2.12 (m, 3H), 3.02 (s, 3H), 3.06-3.21 (m, 1H),3.27 (d, J=7.28 Hz, 2H), 3.29-3.34 (m, 1H), 4.09 (br. s., 1H), 4.18-4.30(m, 2H), 7.26 (d, J=7.53 Hz, 1H), 7.29-7.37 (m, 2H), 7.58 (br. s., 1H),7.68 (d, J=8.53 Hz, 1H), 7.82-7.96 (m, 3H), 7.99-8.08 (m, 2H). LCMS m/z666.32 (M+Na), Rt 2.716 min. HPLC Rt 11.711 min. (Sunfire C18), 98.4%purity and 12.663 min. (XBridge Phenyl C18), 98.8% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(pyrrolidin-2-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide, TFA

To a 10 mL RBF was added dichloroethane (1 mL), tert-butyl242-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-(isobutylcarbamoyl)phenoxy)methyl)pyrrolidine-1-carboxylate(10.2 mg, 15.8 μmol) and TFA, trifluoroacetic acid, (800 mL). Thesolution was stirred for 30 minutes at room temperature, then evaporatedon the rotovap. The product was diluted with dichloroethane andevaporated once more to give a white solid (99% yield). ¹H NMR (400 MHz,CD₃OD) δ ppm 1.04 (d, J=6.53 Hz, 6H), 1.93-2.12 (m, 4H), 2.24-2.37 (m,1H), 3.00 (s, 3H), 3.13-3.22 (m, 1H), 3.25-3.30 (m, 2H), 3.30-3.36 (m,1H), 4.10 (dd, J=7.15, 2.89 Hz, 1H), 4.29 (dd, J=10.67, 7.15 Hz, 1H),4.51 (dd, J=10.54, 3.26 Hz, 1H), 7.28 (d, J=8.53 Hz, 1H), 7.35 (t,J=8.78 Hz, 2H), 7.60 (dd, J=8.53, 1.51 Hz, 1H), 7.73 (d, J=8.53 Hz, 1H),7.92-8.08 (m, 5H). LCMS m/z 544.22 (M+H), Rt 1.577 min. HPLC Rt 6.775min. (Sunfire C18), 99.7% purity and 11.724 min. (XBridge Phenyl C18),100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(pyrrolidin-3-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide, TFA

¹H NMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.78 Hz, 6H), 1.77-1.98 (m,2H), 2.10 (dd, J=13.05, 6.78 Hz, 1H), 2.76-2.86 (m, 1H), 2.88-2.98 (m,3H), 3.18 (t, J=6.40 Hz, 5H), 3.55 (br. s., 1H), 4.02-4.26 (m, 2H), 7.08(d, J=8.53 Hz, 1H), 7.23 (t, J=8.78 Hz, 2H), 7.48 (dd, J=8.53, 1.76 Hz,1H), 7.59 (d, J=8.53 Hz, 1H), 7.70 (t, J=5.77 Hz, 1H), 7.80-7.89 (m,2H), 7.94 (dd, J=9.79, 1.76 Hz, 2H), 7.99 (dd, J=8.91, 5.40 Hz, 2H).HPLC Rt 6.130 min. (Sunfire C18), 98.9% purity and 10.184 min. (XBridgePhenyl C18), 98.6% purity. LCMS m/z 544.18 (M+H), Rt 1.557 min.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(piperidin-3-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide, TFA

¹H NMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.78 Hz, 6H), 1.40-1.57 (m,1H), 1.75-2.00 (m, 4H), 2.33 (br. s., 1H), 2.80-3.00 (m, 5H), 3.18 (t,J=6.40 Hz, 2H), 3.32 (d, J=12.05 Hz, 1H), 3.45 (d, J=10.79 Hz, 1H),3.90-4.12 (m, 2H), 7.03 (d, J=8.53 Hz, 1H), 7.22 (t, J=8.78 Hz, 2H),7.47 (dd, J=8.53, 1.51 Hz, 1H), 7.58 (d, J=8.53 Hz, 1H), 7.71 (t, J=5.65Hz, 1H), 7.75-7.86 (m, 2H), 7.92 (s, 2H), 8.01 (dd, J=8.78, 5.52 Hz,2H). LCMS m/z 558.20 (M+H), Rt 1.595 min. HPLC Rt 6.443 min. (SunfireC18), 99.2% purity and 10.418 min. (XBridge Phenyl C18), 99.2% purity.

5-(2-(3-Amino-3-oxopropoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.88-0.97 (m, 6H), 1.77 (dt, J=6.71, 3.29Hz, 1H), 1.89 (dt, J=13.36, 6.74 Hz, 1H), 2.65 (br. s., 1H), 2.96 (s,3H), 3.10-3.21 (m, 3H), 3.60-3.65 (m, 1H), 6.90 (d, J=8.28 Hz, 1H),7.16-7.25 (m, 2H), 7.48-7.56 (m, 1H), 7.66-7.73 (m, 2H), 7.73-7.80 (m,2H), 7.84 (t, J=5.40 Hz, 1H), 7.89 (br. s., 1H), 7.92-8.03 (m, 3H). LCMSRt 1.835 min., m/z 532.26 (M+H). HPLC Rt 7.465 min. (Sunfire C18), 100%purity and 10.929 min. (XBridge Phenyl C18), 92.9% purity.

2-(4-Fluorophenyl)-5-(2-(2-hydroxyethoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a small screw cap vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(92 mg, 0.2 mmol) in DMF (4 mL),(2-Bromoethoxy)-tert-butyldimethylsilane (0.129 mL, 0.600 mmol), and DBU(0.121 mL, 0.800 mmol). The vial was capped and shaken at 80° C.overnight. The DMF was removed under a stream of nitrogen to give a tanoil which was taken up in 6 mL of acetonitrile and purified using aShimadzu preparative HPLC employing acetonitrile/water/10 mM ammoniumacetate where solvent A was 5% acetonitrile/95% H₂O/10 mM ammoniumacetate and solvent B was 5% H₂O/95% acetonitrile/10 mM ammonium acetatewith a Phenomenex-Luna 10 μm C18 30×100 mm column at a gradient of40-100% B and a flow rate of 30 mL/min. over 8 minutes with a 10 minutehold. The solvent was removed on the rotovap to give 44 mgs of the TBSprotected alcohol as a clear colorless oil. LCMS m/z 619.47 (M+H), Rt3.123 min., 96% purity. To the TBS protected alcohol was then added 2.5mL of tetrahydrofuran along with 2 eq. of 1 M HCl solution (0.14 mmol,140 μL). The mixture was stirred for 1 hour at room temperature. Thereaction mixture was transferred to a separatory funnel, diluted withethyl acetate, washed with sodium bicarbonate, brine and dried overmagnesium sulfate. The organic solvent was evaporated and the productplaced under vacuum. The crude product was diluted with 2 mL ofacetonitrile, and purified using a Shimadzu preparative HPLC employingacetonitrile/water/ammonium acetate where solvent A was 5%acetonitrile/95% H₂O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate with a Xbridge C18 5 μm OBD 19×100mm column at a gradient of 30-100% B and a flow rate of 20 mL/min. over7 minutes with a 13 minute hold. 18.3 mgs of a white solid (17% yield, 2steps) was obtained after solvent evaporation. ¹H NMR (400 MHz, THF-d8)δ ppm 0.93 (d, J=6.78 Hz, 6H), 1.80-1.98 (m, 1H), 2.91 (d, J=4.77 Hz,3H), 3.13-3.23 (m, 2H), 3.79 (t, J=4.89 Hz, 2H), 4.10 (t, J=4.89 Hz,2H), 7.08 (d, J=8.53 Hz, 1H), 7.21 (t, J=8.78 Hz, 2H), 7.52 (br. s.,1H), 7.52-7.54 (m, 2H), 7.59 (br. s., 1H), 7.84 (dd, J=8.53, 2.26 Hz,1H), 7.92 (d, J=2.26 Hz, 1H), 8.02 (s, 1H), 8.09-8.20 (m, 2H). LCMS m/z505.36 (M+H), Rt 2.013 min. HPLC Rt 8.901 min. (Sunfire C18), 92.5%purity and 11.479 min. (XBridge Phenyl C18), 92.0% purity. The LC/MSdata was obtained on a Shimadzu analytical LC/Micromass Platform LC(ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 254 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute.

5-(2-(2-Aminoethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 2 dram vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (92.0 mg, 0.20 mmol) in 3 mL of DMF along with2-(2-bromoethyl) isoindoline-1,3-dione (152 mg, 0.600 mmol) and DBU(0.120 mL, 0.800 mmol). The vial was capped and shaken at 75° C. overnight. The crude reaction mixture was then evacuated to near dryness,taken up in 6 mL of acetonitrile and purified using a Shimadzupreparative HPLC employing acetonitrile/water/0.1% TFA where solvent Awas 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent Bwas 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a WatersSunfire 5 μm C18 30×100 mm column at a gradient of 40-100% B and a flowrate of 40 mL/min. over 10 minutes with a 10 minute hold to give5-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide asa white solid (30 mgs, 23% yield). ¹H NMR (400 MHz, DMF-d₇) δ ppm 0.93(d, J=6.78 Hz, 6H), 1.86-1.99 (m, 1H), 2.97 (d, J=4.77 Hz, 3H),3.14-3.26 (m, 2H), 4.06 (t, J=5.90 Hz, 2H), 4.47 (t, J=5.90 Hz, 2H),7.33 (d, J=9.29 Hz, 1H), 7.36-7.49 (m, 4H), 7.74-7.86 (m, 5H), 7.97-8.02(m, 2H), 8.11-8.17 (m, 2H), 8.20 (d, J=4.27 Hz, 1H), 8.42 (s, 1H). LCMSm/z 634.25 (M+H), Rt 2.408 min. HPLC Rt 9.339 min. (Sunfire C18), 100%purity and 11.696 min. (Gemini C18), 98.9% purity. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 254 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 30-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters XBridgePhenyl C18 3 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 30-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. To a 100 mL RBFfitted with a reflux condenser was added5-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(26.4 mg, 0.042 mmol) in methanol and anhydrous hydrazine (1.308 μL,0.042 mmol) solution (Aldrich, 215155-50G). The flask was placed in apre-equilibrated oil bath and refluxed for 2 hours. The crude productwas concentrated on the rotovap to remove methanol, diluted withdichloromethane, washed with a 0.5M sodium hydroxide solution andextracted. The solvent was removed and the crude product was purifiedusing the Shimadzu preparative HPLC employing acetonitrile/water/0.1%TFA mentioned above with a gradient of 20-100% B to give (13 mgs, 58%)of a white solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.94 (d, J=6.78 Hz, 6H),1.91 (dt, J=13.55, 6.78 Hz, 1H), 2.91 (s, 3H), 3.18 (d, J=7.28 Hz, 2H),3.33 (t, J=5.02 Hz, 2H), 4.30 (t, J=5.14 Hz, 2H), 7.21 (d, J=8.78 Hz,1H), 7.26 (t, J=8.78 Hz, 2H), 7.50-7.59 (m, 1H), 7.60-7.68 (m, 1H),7.81-8.00 (m, 5H). LCMS m/z 504.31 (M+H), Rt 1.538 min. HPLC Rt 6.435min. (Sunfire C18), 97.1% purity and 11.376 min. (XBridge Phenyl C18),100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-ureidoethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

To a 2 dram vial was added5-(2-(2-aminoethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(22.7 mg, 0.045 mmol) in ethanol (2 mL) along with water (0.667 mL) andpotassium cyanate (5.34 μL, 0.135 mmol). The vial was sealed and themixture heated to 80° C. with shaking for 24 hours. 3 additionalequivalents of potassium cyanate was added to the reaction mixture andthe vial re-capped and heated for 3 days. The crude reaction mixture wasevaporated, diluted with acetonitrile, filtered and purified using aShimadzu preparative HPLC employing acetonitrile/water/0.1% TFA wheresolvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid witha Waters Sunfire 5 μm C18 30×100 mm column at a gradient of 30-100% Band a flow rate of 40 mL/min. over 8 minutes with a 6 minute hold. Thesolvent was evaporated to give 10 mgs (40%) of a white solid. The LC/MSdata was obtained on a Shimadzu analytical LC/Micromass Platform LC(ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% TFA/10% HPLC grade water), (A=90% HPLC gradewater/0.1% TFA/10% HPLC grade acetonitrile), in 3 minutes with a 1minute hold at a rate of 4 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 20-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Phenomenex Gemini C18 3 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of20-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 0.94 (d, J=6.53 Hz, 6H),1.82-1.98 (m, 1H), 2.88 (d, J=4.77 Hz, 3H), 3.14-3.23 (m, 2H), 3.47 (q,J=4.94 Hz, 2H), 4.03 (t, J=4.52 Hz, 2H), 5.55 (br. s., 1 H), 6.18 (br.s., 1H), 7.03 (d, J=8.53 Hz, 1H), 7.21-7.32 (m, 2H), 7.46-7.51 (m, 1H),7.51-7.56 (m, 1H), 7.56-7.62 (m, 1H), 7.80 (dd, J=8.53, 2.26 Hz, 1H),7.84 (d, J=4.52 Hz, 1H), 7.91-8.02 (m, 3H), 8.22 (d, J=1.25 Hz, 1H).LCMS Rt 1.988 min., m/z 547.24 (M+H). HPLC Rt 8.126 min. (Sunfire C18),99.7% purity and 11.214 min. (Gemini C18), 99.5% purity.

5-(2-(3-(1,3-Dioxoisoindolin-2-yl)propoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.78 Hz, 6H), 1.81-1.97 (m,1H), 2.09 (m, 2H), 2.90 (d, J=4.77 Hz, 3H), 3.12-3.26 (m, 2H), 3.79 (t,J=6.65 Hz, 2H), 4.11 (t, J=5.90 Hz, 2 H), 7.03 (d, J=8.78 Hz, 1H),7.16-7.28 (m, 2H), 7.45 (d, J=4.27 Hz, 1H), 7.48-7.51 (m, 1H), 7.51-7.56(m, 1H), 7.59 (dd, J=8.78, 1.76 Hz, 1H), 7.65-7.74 (m, 4 H), 7.79-7.90(m, 3H), 8.08-8.24 (m, 2H). LCMS m/z 648.19 (M+H), Rt 2.458 min. HPLC Rt10.158 min. (Sunfire C18), 99.4% purity and 12.111 min. (Gemini C18),99.7% purity.

5-(2-(2-Aminoethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.53 Hz, 6H), 1.82-1.93 (m,1H), 2.15 (m, 2H), 2.91 (d, J=4.52 Hz, 3H), 3.08-3.24 (m, 4H), 4.17 (t,J=5.65 Hz, 2H), 7.06 (d, J=8.53 Hz, 1H), 7.18-7.28 (m, 2 H), 7.47 (dd,J=8.53, 1.76 Hz, 1H), 7.53-7.66 (m, 2H), 7.82 (dd, J=8.53, 2.26 Hz, 2H),7.90 (d, J=2.26 Hz, 1H), 7.95 (d, J=1.51 Hz, 1H), 7.97-8.05 (m, 2H),8.28 (br. s., 2H). LCMS Rt 1.537 min., m/z 518.16 (M+H). HPLC Rt 10.734min. (Sunfire C18), 99.2% purity and 10.881 min. (Gemini C18), 99.3%purity. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Sunfire 5 μm C18 4.6×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of4 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a PhenomenexGemini C18 3 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute.

5-(2-(Difluoromethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a small microwave vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(23.02 mg, 0.05 mmol), acetonitrile (400 μL), water (400 μL), and2-chloro-2,2-difluoro-1-phenylethanone (47.6 mg, 0.250 mmol). The vialwas sealed and the reaction mixture subjected to microwave heating(Biotage Initiator) at 110° C. for 8 minutes. The crude reaction mixturewas further diluted with acetonitrile, filtered, and purified using aShimadzu preparative HPLC employing acetonitrile/water/0.1% TFA wheresolvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid witha Waters Sunfire 5 μm C18 30×100 mm column at a gradient of 30-100% Band a flow rate of 40 mL/min. over 10 minutes with a 10 minute hold. Thesolvent was evaporated to give product (35%) as a white solid. ¹H NMR(500 MHz, THF-d8) δ ppm 0.86-1.01 (m, 6H), 1.89 (dt, J=13.50, 6.83 Hz,1H), 2.90 (d, J=4.58 Hz, 3H), 3.12-3.28 (m, 2H), 6.61-7.04 (m, 1H),7.18-7.27 (m, 2H), 7.31 (d, J=8.54 Hz, 1H), 7.49 (dd, J=8.55, 1.83 Hz,1H), 7.53 (d, J=4.27 Hz, 1H), 7.59 (d, J=8.55 Hz, 1H), 7.78 (t, J=5.49Hz, 1H), 7.82 (d, J=1.22 Hz, 1H), 7.91 (dd, J=8.55, 2.44 Hz, 1H), 7.98(d, J=2.14 Hz, 1H), 8.09-8.17 (m, 2H). LCMS m/z 511.21 (M+H), Rt 2.393min. HPLC Rt 12.213 min. (Sunfire C18), 99.3% purity and 15.427 min.(XBridge C18), 99.8% purity. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 3 minutes with a 1 minute hold ata rate of 4 mL/minute. HPLC purity was determined using a Shimadzuanalytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm4.6×150 mm column employing water/acetonitrile/0.1% TFA with a gradientof 30-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersPhenyl XBridge C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 30-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute.

3-Bromo-N-isobutyl-5-isopropoxybenzamide

To a large screw top vial was added 3-bromo-5-hydroxybenzoic acid (1 g,4.61 mmol), pyridine (10 mL),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine, HCl (0.972g, 5.07 mmol) (EDAC) along with 2-methylpropan-1-amine (0.504 mL, 5.07mmol). The vial was capped and the mixture shaken over night. Thereaction mixture was acidified with 10 mL of an ice cold 1 M HClsolution. The mixture was diluted with dichloromethane, extracted,washed with brine and dried over magnesium sulfate. The reaction mixturewas filtered then added to the top of a 240 g Thomson silica gelcartridge. The product was eluted with 0-12% (3000 mL) methanol indichloromethane to give 3-bromo-5-hydroxy-N-isobutylbenzamide (95%) as ayellow solid. LCMS Rt 1.632 min., m/z 273.99 (M+H), 93% purity. TheLC/MS data was obtained on a Shimadzu analytical LC/Micromass PlatformLC (ESI+) at 220 nm using the following set of conditions: WatersSunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90%HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water),(A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 3 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 30-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. To a sealed tube was added3-bromo-5-hydroxy-N-isobutylbenzamide (380.4 mg, 1.398 mmol), DMF (15mL), 2-iodopropane (0.210 mL, 2.097 mmol), and potassium carbonate (290mg, 2.097 mmol). The tube was sealed and heated to 90° C. overnight. Thereaction mixture was cooled, transferred to a separatory funnel, dilutedwith ethyl acetate and extracted. The organic solution was washed with1M HCl, brine, dried over magnesium sulfate, filtered and evaporated todryness. The resulting orange oil was taken up in dichloromethane andpurified using the Biotage Horizon with a 110 g Thomson silica gelcolumn employing 0-5% methanol and 2000 mL of solvent to give a nearquantitative yield of 3-bromo-N-isobutyl-5-isopropoxybenzamide as alight yellow solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 3 minutes with a 1 minute hold at a rate of4 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 30-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.87-1.04 (m, 6H), 1.23-1.37(m, 6H), 1.79-2.00 (m, 1H), 3.25 (t, J=6.40 Hz, 2H), 4.57 (dt, J=12.05,6.02 Hz, 1H), 6.29 (br. s., 1H), 7.08-7.19 (m, 1H), 7.21-7.26 (m, 1H),7.38 (s, 1H). LCMS Rt 2.413 min., m/z 315.01 (M+H), 95% purity.

3-Bromo-N-isobutyl-4-(trifluoromethoxy)benzamide

To a large screw top vial was added previously synthesized3-bromo-4-(trifluoromethoxy)benzoic acid (100 mg, 0.351 mmol), pyridine(5 mL), 2-methylpropan-1-amine (0.038 mL, 0.386 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine, HCl (EDAC)(74.0 mg, 0.386 mmol) and HATU,2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (400 mg, 1.053 mmol). The vial was capped and shakenovernight at room temperature. The crude reaction mixture was dilutedwith methanol and purified using a Shimadzu preparative HPLC employingmethanol/water/0.1% TFA where solvent A was 10% methanol/90% water/0.1%trifluoroacetic acid and solvent B was 10% water/90% methanol/0.1%trifluoroacetic acid with a Phenomenex-Luna 10 μm C18 30×100 mm columnat a gradient of 30-100% B and a flow rate of 40 mL/min. over 9 minuteswith a 11 minute hold to give 75 mgs (62%) of a yellow solid. The LC/MSdata was obtained on a Shimadzu analytical LC/Micromass Platform LC(ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 254 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a PhenomenexGemini C18 3 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,CD₃OD) δ ppm 0.98-1.11 (m, 6H), 1.91-2.09 (m, 1H), 3.22-3.30 (m, 2H),7.57 (dd, J=8.53, 1.51 Hz, 1H), 7.96 (dd, J=8.53, 2.26 Hz, 1H), 8.25 (d,J=2.01 Hz, 1H), 8.68 (br. s., 1H). HPLC Rt 17.141 min. (Sunfire C18),99.5% purity and 15.912 min. (Gemini C18), 100% purity. LCMS Rt 2.367min., m/z 341.99 (M+H).

3-Bromo-N-(1-phenylcyclopropyl)-4-(trifluoromethoxy)benzamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.40 (d, J=4.52 Hz, 4H), 7.16-7.30 (m,1H), 7.32-7.41 (m, 4H), 7.58 (dd, J=8.66, 1.38 Hz, 1H), 7.99 (dd,J=8.66, 2.13 Hz, 1H), 8.28 (d, J=2.01 Hz, 1H), 9.42 (br. s., 1H). LCMSRt 2.56 min., m/z 401.97 (M+H). HPLC Rt 15.171 min. (Sunfire C18), 98.8%purity and 16.066 min. (Gemini C18), 100% purity.

3-Bromo-N-(1-(pyridin-2-yl)cyclopropyl)-4-(trifluoromethoxy)benzamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.70-1.80 (m, 2H), 1.80-1.91 (m, 2H), 7.57(dd, J=8.78, 1.25 Hz, 1H), 7.76-7.88 (m, 2H), 8.03 (dd, J=8.53, 2.26 Hz,1H), 8.33 (d, J=2.01 Hz, 1H), 8.43 (t, J=8.03 Hz, 1H), 8.63 (d, J=5.52Hz, 1H). LCMS Rt 1.420 min, m/z 402.95 (M+H). HPLC Rt 5.611 min.(Sunfire C18), 93.8% purity and 11.206 min. (Gemini C18), 98.4% purity.

2-(4-Fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide

To a sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (2.000 g, 4.79 mmol), dioxane (20 mL), triethylamine(1.993 mL, 14.38 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.87 g,19.17 mmol), and finally PdCl₂(dppf) (0.235 g, 0.144 mmol). The vial wasflushed with N₂, sealed and heated overnight in an oil bath at 80° C.The reaction mixture was cooled, diluted with dichloromethane, andwashed with a 0.1M HCl solution then brine. The brown mixture was pulledthrough a plug of 1:1 magnesium sulfate/celite to give a dark brownsolid after solvent evaporation. The crude product was taken up in 50 mLof dichloromethane and added to the top of a pre-equilibrated 240 gThomson silica gel cartridge. The product was eluted with 0-2% methanolin dichloromethane to give a 80% yield of2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamideas a tan solid. ¹H NMR (400 MHz, THF-d8) δ ppm 1.34 (s, 12H), 2.92-2.95(m, 3H), 7.20 (t, J=8.91 Hz, 2H), 7.50 (d, J=8.28 Hz, 2H), 7.74 (dd,J=8.28, 1.00 Hz, 1H), 8.08-8.13 (m, 2H), 8.14 (s, 1 H). LCMS m/z 396.18(M+H), Rt 2.455 min., 90% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-isopropoxyphenyl)-N-methylbenzofuran-3-carboxamide

To a medium sized microwave vial was added 1 (465 mg, 1.0 mmol), dioxane(15 mL), water (1.500 mL), 3-bromo-N-isobutyl-5-isopropoxybenzamide (377mg, 1.200 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (82mg, 0.200 mmol), potassium phosphate, tribasic (849 mg, 4.00 mmol) andfinally palladium(II) acetate (44.9 mg, 0.200 mmol). The vial was cappedand subjected to microwave heating (150° C.) in a Biotage Initiator for13 minutes. The reaction mixture was diluted with 150 mL ofdichloromethane, washed with a 1M HCl solution, then water and finallybrine. The solution was filtered through pad of 1:1 celite/magnesiumsulfate then evaporated to give a brown oil. The crude product was takenup in dichloromethane and added to the top of a pre-equilibrated 100 gBiotage silica gel cartridge. The product was eluted with a 0-3%methanol in dichloromethane solvent mixture to give product as a lighttan solid (51%). ¹H NMR (400 MHz, THF-d8) δ ppm 0.95 (d, J=6.53 Hz, 6H),1.35 (d, J=6.02 Hz, 6H), 1.83-1.98 (m, 1H), 2.90-2.98 (m, 3H), 3.14-3.29(m, 2H), 4.66-4.82 (m, 1H), 7.18-7.25 (m, 2H), 7.26-7.29 (m, 1H),7.38-7.42 (m, 1H), 7.48 (m, 1H), 7.58-7.65 (m, 2H), 7.65-7.72 (m, 2H),7.96 (d, J=1.00 Hz, 1H), 8.08-8.16 (m, 2H). LCMS Rt 2.588 min., m/z503.25 (M+H), 98% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(trifluoromethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade acetonitrile/0.1% TFA/10% HPLC grade water), (A=90%HPLC grade water/0.1% TFA/10% HPLC grade acetonitrile), in 3 minuteswith a 1 minute hold at a rate of 4 mL/minute. HPLC purity wasdetermined using a Shimadzu analytical LC at 254 nm and 256 nm with aWaters Sunfire C18 3.5 mm 4 6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 10-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a PhenomenexPhenyl Xbridge C18 3.5 mm 4 6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 0.94 (dd, J=6.78, 2.26 Hz, 6H), 1.82-1.97 (m, 1H), 2.90(d, J=4.77 Hz, 3H), 3.12-3.24 (m, 2H), 7.17-7.29 (m, 2H), 7.47 (dd,J=8.53, 1.76 Hz, 2H), 7.61 (d, J=8.53 Hz, 1H), 7.71-7.81 (m, 2H), 7.83(d, J=1.26 Hz, 1H), 7.92-7.98 (m, 1H), 7.99-8.05 (m, 1H), 8.07-8.15 (m,2H). LCMS Rt 2.565 min., m/z 529.13 (M+H). HPLC Rt 11.166 min. (SunfireC18), 99.5% purity and 11.813 min. (Phenyl Xbridge C18), 86.7% purity.

2-(4-Fluorophenyl)-N-methyl-5-(5-(1-phenylcyclopropylcarbamoyl)-2-(trifluoromethoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.20-1.39 (m, 4H), 2.89 (d, J=4.52 Hz,3H), 7.06-7.15 (m, 1H), 7.17-7.27 (m, 4H), 7.29-7.35 (m, 2H), 7.44 (br.s., 1H), 7.47 (m, 2H), 7.61 (d, J=8.53 Hz, 1H), 7.83 (d, J=1.26 Hz, 1H),7.98 (dd, J=8.66, 2.38 Hz, 1H), 8.05 (d, J=2.01 Hz, 1H), 8.08-8.15 (m,2H), 8.50 (br. s., 1H). LCMS Rt 2.796 min., m/z 589.23 (M+H). HPLC Rt11.419 min. (Sunfire C18), 98.9% purity and 12.424 min. (Phenyl XbridgeC18), 100% purity.

2-(4-Fluorophenyl)-N-methyl-5-(5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-2-(trifluoromethoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.21-1.33 (m, 2H), 1.62-1.70 (m, 2H),2.89 (d, J=4.77 Hz, 3H), 7.01 (m, 1H), 7.18-7.28 (m, 2H), 7.40 (d,J=8.03 Hz, 1H), 7.43 (br. s., 1H), 7.46-7.58 (m, 3H), 7.62 (d, J=8.53Hz, 1H), 7.86 (d, J=1.26 Hz, 1H), 8.04 (dd, J=8.66, 2.38 Hz, 1H),8.07-8.17 (m, 3H), 8.36-8.42 (m, 1H), 8.57 (br. s., 1H). LCMS Rt 1.768min., m/z 590.13 (M+H). HPLC Rt 7.645 min. (Sunfire C18), 99.0% purityand 12.041 min. (Phenyl Xbridge C18), 99.9% purity.

2-(4-Fluorophenyl)-5-(3-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a 250 mL RBF was added2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-isopropoxyphenyl)-N-methylbenzofuran-3-carboxamide(1.3409 g, 2.67 mmol) in dichloromethane (20 mL). The flask was sealedwith a septa, placed under N₂ and stirred for 5 minutes. To this mixturewas then added (cold) 1M trichloroborane (8.00 mL, 8.00 mmol) indichloromethane. The solution was stirred at room temperature for 6hours. The reaction mixture was cooled to 0° C. and methanol was addedto quench the reaction. The flask was allowed to warm to roomtemperature and the volatiles were removed to give a quantitative yieldof a tan solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.78 Hz, 6H),1.97-2.12 (m, 1H), 3.01-3.12 (m, 3H), 3.29 (t, J=6.53 Hz, 2H), 7.27-7.40(m, 4 H), 7.64 (s, 1H), 7.72 (s, 2H), 7.98 (s, 1H), 8.03 (dd, J=8.66,5.40 Hz, 2H), 8.56 (br. s., 1H). LCMS Rt 2.157 min., m/z 461.03 (M+H),97.6% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-methoxyphenyl)-N-methylbenzofuran-3-carboxamide

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 3 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% TFA with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Waters PhenylXBridge C18 3.5 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 0.87-1.03 (m, 6H), 1.83-1.99 (m, 1H), 2.93 (d, J=4.77 Hz,3H), 3.16-3.25 (m, 2H), 3.88 (s, 3H), 7.18-7.26 (m, 2H), 7.29-7.32 (m,1H), 7.42 (dd, J=2.38, 1.38 Hz, 1H), 7.50 (br. s., 1H), 7.57-7.66 (m,2H), 7.71 (br. s., 2H), 7.97 (d, J=1.25 Hz, 1H), 8.08-8.16 (m, 2H). LCMSm/z 475.22 (M+H), Rt 2.373 min. HPLC Rt 10.268 min. (Sunfire C18), 96.7%purity and 12.104 min. (XBridge Phenyl C18), 99.2% purity.

5-(3-(2-(Dimethylamino)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.95 (d, J=6.78 Hz, 6H), 1.87-1.98 (m,1H), 2.89 (s, 6H), 2.93 (d, J=4.52 Hz, 3H), 3.21 (t, J=6.40 Hz, 2H),3.47-3.54 (m, 2H), 4.54-4.64 (m, 2H), 7.22 (t, J=8.66 Hz, 2H), 7.42 (s,1H), 7.51 (br. s., 1H), 7.58 (d, J=5.27 Hz, 1H), 7.61 (s, 1H), 7.62-7.69(m, 1H), 7.80 (s, 1H), 7.83 (br. s., 1H), 7.98 (s, 1H), 8.12 (dd,J=8.91, 5.40 Hz, 2H). LCMS Rt 1.543 min., m/z 532.28 (M+H). HPLC Rt6.816 min. (Sunfire C18), 96.0% purity and 12.073 min. (Phenyl XbridgeC18), 98.2% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(2-(pyridin-3-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.94 (d, J=6.53 Hz, 6H), 1.83-1.98 (m,1H), 2.92 (d, J=4.27 Hz, 3H), 3.13-3.30 (m, 4H), 4.32-4.47 (m, 2H), 7.22(t, J=8.66 Hz, 2H), 7.32 (s, 1H), 7.41-7.53 (m, 3 H), 7.55-7.67 (m, 2H),7.72 (br. s., 2H), 7.91-8.01 (m, 2H), 8.11 (dd, J=8.03, 5.52 Hz, 2H),8.55 (br. s., 1H), 8.72 (br. s., 1H). LCMS Rt 1.632 min., m/z 566.26(M+H). HPLC Rt 7.216 min. (Sunfire C18), 98.1% purity and 12.073 min.(Phenyl Xbridge C18), 99.0% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(2-(piperidin-3-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

The LC/MS data was obtained on a Waters Acquity SDS analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Acquity HPLC BEH 1.7 μm C18, 2.1×50 mm column, with agradient of 2-98% B (B=100% HPLC grade acetonitrile/0.05% TFA), (A=100%HPLC grade water/0.05% TFA), in 2.2 minutes at a rate of 0.8 mL/minute.HPLC purity was determined using a Shimadzu analytical LC at 254 nm and256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 20-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.99 (d, J=6.78 Hz, 6H), 1.36(dd, J=12.30, 3.01 Hz, 1H), 1.69-1.89 (m, 3H), 1.91-2.16 (m, 4H), 2.77(t, J=12.17 Hz, 1H), 2.87-2.95 (m, 1H), 3.23 (d, J=7.03 Hz, 2H),3.29-3.40 (m, 4H), 3.43-3.52 (m, 1H), 4.19 (t, J=6.02 Hz, 2H), 7.24 (t,J=8.78 Hz, 2H), 7.36 (dd, J=10.54, 1.51 Hz, 2H), 7.58-7.68 (m, 2H), 7.70(s, 1H), 7.87-7.98 (m, 3H). LCMS m/z 572.16 (M+H). HPLC Rt 6.518 min.(Sunfire C18), 98% purity.

5-(3-(4-Aminobutoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 0.99 (d, J=6.78 Hz, 6H), 1.86-2.04 (m,5H), 2.95-3.00 (m, 3H), 3.06 (t, J=7.15 Hz, 2H), 3.21-3.27 (m, 2H), 4.19(t, J=5.40 Hz, 2H), 7.23-7.31 (m, 2H), 7.38 (dd, J=3.76, 1.25 Hz, 2H),7.64-7.70 (m, 2H), 7.71 (s, 1H), 7.91-7.99 (m, 3H), 8.60 (br. s., 1 H).LCMS m/z 532.00 (M+H). HPLC Rt 6.386 min. (Sunfire C18), 100% purity.

5-(3-(2-(1H-imidazol-1-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.78 Hz, 6H), 2.03 (d, J=6.78Hz, 1H), 3.05 (s, 3H), 3.31 (d, J=7.03 Hz, 2H), 4.62 (t, J=4.77 Hz, 2H),4.79 (br. s., 2H), 7.35 (t, J=8.78 Hz, 2H), 7.49 (d, J=2.76 Hz, 2H),7.68 (s, 1H), 7.73-7.77 (m, 2H), 7.83 (s, 1H), 7.88 (s, 1H), 7.98-8.07(m, 3H), 9.17 (s, 1H). LCMS m/z 555.00 (M+H). HPLC Rt 6.295 min.(Sunfire C18), 95.2% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(2-(pyridin-4-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.05 (d, J=6.53 Hz, 6H), 1.95-2.09 (m,1H), 3.04 (s, 3H), 3.24-3.33 (m, 2H), 3.54 (t, J=5.90 Hz, 2H), 4.60 (t,J=5.77 Hz, 2H), 7.27-7.38 (m, 2H), 7.41-7.49 (m, 2H), 7.71-7.75 (m, 2H),7.78 (t, J=1.51 Hz, 1H), 7.96-8.05 (m, 3H), 8.12 (d, J=6.53 Hz, 2H),8.80 (d, J=6.78 Hz, 2H). LCMS m/z 566.00 (M+H). HPLC Rt 6.4921 min.(Sunfire C18), 98.6% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(prop-2-ynyloxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.07 (d, J=6.78 Hz, 6H), 1.94-2.18 (m,1H), 3.00-3.13 (m, 4H), 3.30 (d, J=7.03 Hz, 2H), 4.94-4.98 (m, 2H),7.27-7.42 (m, 2H), 7.47-7.59 (m, 2H), 7.68-7.79 (m, 2H), 7.82 (t, J=1.51Hz, 1H), 7.98-8.11 (m, 3H). LCMS m/z 499.00 (M+H). HPLC Rt 9.984 min.(Sunfire C18), 99.4% purity.

5-(3-(Cyclopropylmethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 0.48 (d, J=14.81 Hz, 2H), 0.72 (d, J=7.78Hz, 2H), 1.06 (d, J=6.53 Hz, 6H), 1.51-1.59 (m, 1H), 1.98-2.10 (m, 1H),3.05 (s, 3H), 3.30 (d, J=7.03 Hz, 2H), 4.04 (d, J=6.78 Hz, 2H), 7.33 (t,J=8.66 Hz, 2H), 7.43 (s, 2H), 7.49 (br. s., 1H), 7.75 (d, J=9.04 Hz,3H), 7.97-8.09 (m, 3H). LCMS m/z 515.17 (M+H). HPLC Rt 10.878 min.(Sunfire C18), 91.4% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(pyridin-3-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.78 Hz, 6H), 2.03 (dt,J=13.55, 6.78 Hz, 1H), 3.04 (s, 3H), 3.30 (d, J=7.03 Hz, 2H), 5.52 (s,2H), 7.33 (t, J=8.78 Hz, 2H), 7.59 (dd, J=6.40, 1.38 Hz, 2H), 7.69-7.80(m, 2H), 7.84 (s, 1H), 7.96-8.09 (m, 4H), 8.64 (d, J=8.28 Hz, 1H), 8.83(d, J=4.52 Hz, 1H), 9.02 (s, 1H). LCMS m/z 552.05 (M+H). HPLC Rt 6.401min. (Sunfire C18), 100% purity.

2-(4-Fluorophenyl)-5-(3-(furan-3-ylmethoxy)-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.53 Hz, 6H), 1.96-2.14 (m,1H), 3.06 (s, 3H), 3.30 (d, J=7.03 Hz, 2H), 5.19 (s, 2H), 6.64 (s, 1H),7.33 (t, J=8.78 Hz, 2H), 7.51 (s, 2H), 7.59 (br. s., 1H), 7.70-7.82 (m,4H), 8.01 (d, J=11.54 Hz, 3H). LCMS m/z 541.00 (M+H). HPLC Rt 10.426min. (Sunfire C18), 90.0% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(2-(piperidin-4-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.53 Hz, 6H), 1.96-2.14 (m,1H), 3.06 (s, 3H), 3.30 (d, J=7.03 Hz, 2H), 5.19 (s, 2H), 6.64 (s, 1H),7.33 (t, J=8.78 Hz, 2H), 7.51 (s, 2H), 7.59 (br. s., 1H), 7.70-7.82 (m,4H), 8.01 (d, J=11.54 Hz, 3H). LCMS m/z 572.17 (M+H). HPLC Rt 6.571 min.(Sunfire C18), 95.8% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-propoxyphenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.87-0.98 (m, 6H), 1.07 (t, J=7.40 Hz,3H), 1.79-1.96 (m, 3H), 2.93 (d, J=4.52 Hz, 3H), 3.21 (t, J=6.40 Hz,2H), 4.05 (t, J=6.53 Hz, 2H), 7.22 (t, J=8.66 Hz, 2H), 7.30 (br. s.,1H), 7.39-7.56 (m, 2H), 7.56-7.79 (m, 4H), 7.97 (s, 1H), 8.12 (dd,J=8.53, 5.52 Hz, 2H). LCMS m/z 503.15 (M+H). HPLC Rt 11.141 min.(Sunfire C18), 98.9% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-ethoxyphenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.78 Hz, 6H), 1.47-1.62 (m,3H), 1.92-2.15 (m, 1H), 3.05 (s, 3H), 3.30 (d, J=7.03 Hz, 2H), 4.26 (q,J=6.94 Hz, 2H), 7.33 (t, J=8.78 Hz, 2H), 7.43 (s, 2H), 7.70-7.83 (m,3H), 7.97-8.09 (m, 3H). LCMS m/z 489.00 (M+H). HPLC Rt 10.464 min.(Sunfire C18), 93.7% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(2-methoxyethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.86-1.05 (m, 6H), 1.82-2.02 (m, 1H),2.86-3.04 (m, 3H), 3.21 (t, J=6.40 Hz, 2H), 3.34-3.45 (m, 3H), 3.72 (t,J=4.77 Hz, 2H), 4.21 (t, J=4.77 Hz, 2H), 7.22 (t, J=8.78 Hz, 2H), 7.33(s, 1H), 7.42 (s, 1H), 7.49 (br. s., 1H), 7.55-7.83 (m, 4H), 7.97 (s,1H), 8.12 (dd, J=8.78, 5.52 Hz, 2H). LCMS m/z 519.10 (M+H). HPLC Rt9.676 min. (Sunfire C18), 100% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 0.99 (d, J=6.53 Hz, 6H), 1.90-2.03 (m,1H), 2.78 (s, 3H), 2.94-3.02 (m, 3H), 3.23 (d, J=7.03 Hz, 2H), 4.53 (t,J=4.89 Hz, 2H), 4.65 (t, J=4.89 Hz, 2H), 7.22-7.32 (m, 2H), 7.38 (d,J=1.51 Hz, 2H), 7.46 (d, J=2.01 Hz, 1H), 7.63-7.69 (m, 3H), 7.75 (t,J=1.51 Hz, 1H), 7.91-8.00 (m, 3H). LCMS m/z 569.12 (M+H). HPLC Rt 6.340min. (Sunfire C18), 100% purity.

(S)-2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-(pyrrolidin-2-ylmethoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, CD₃OD) δ ppm 1.06 (d, J=6.78 Hz, 6H), 1.98-2.12 (m,2H), 2.16-2.32 (m, 2H), 2.34-2.48 (m, 1H), 3.04 (s, 3H), 3.31 (d, J=7.03Hz, 2H), 3.44-3.55 (m, 2H), 4.12-4.22 (m, 1H), 4.34 (dd, J=10.54, 8.28Hz, 1H), 4.51-4.62 (m, 1H), 7.27-7.42 (m, 2H), 7.49-7.59 (m, 2H),7.71-7.82 (m, 2H), 7.85 (s, 1H), 7.97-8.10 (m, 3H). LCMS m/z 544.12(M+H). HPLC Rt 6.326 min. (Sunfire C18), 95.8% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-((5-methylisoxazol-3-yl)methoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.92-0.99 (m, 6H), 1.83-1.99 (m, 1H),2.40 (s, 3H), 2.90-2.98 (m, 3H), 3.17-3.27 (m, 2H), 5.18-5.25 (m, 1H),6.17-6.25 (m, 1H), 7.17-7.27 (m, 2H), 7.41-7.46 (m, 1H), 7.47-7.54 (m,2H), 7.57-7.68 (m, 3H), 7.68-7.74 (m, 1H), 7.76 (d, J=1.51 Hz, 1H), 7.98(d, J=1.26 Hz, 1H), 8.07-8.19 (m, 2H). LCMS m/z 556.00 (M+H). HPLC Rt10.106 min. (Sunfire C18), 90.0% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-((5-methylisoxazol-3-yl)methoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, THF-d8) δ ppm 0.98 (d, J=6.71 Hz, 6H), 1.88-2.01 (m,1H), 2.92-3.00 (m, 3H), 3.20-3.27 (m, 2H), 5.17 (s, 2H), 6.42 (dd,J=3.05, 1.83 Hz, 1H), 6.53 (d, J=3.36 Hz, 1H), 7.21-7.30 (m, 3H), 7.43(d, J=1.53 Hz, 1H), 7.55 (d, J=12.51 Hz, 1H), 7.59-7.66 (m, 3H),7.67-7.71 (m, 1H), 7.78 (s, 1H), 8.02 (s, 1H), 8.13-8.18 (m, 2H). LCMSm/z 541.17 (M+H). HPLC Rt 10.401 min. (Sunfire C18), 90.0% purity.

5-(3-(Cyclobutylmethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, THF-d8) δ ppm 0.95 (d, J=6.71 Hz, 6H), 1.86-2.02 (m,6H), 2.10-2.21 (m, 2H), 2.87-2.97 (m, 3H), 3.20 (d, J=6.71 Hz, 2H), 4.07(d, J=6.71 Hz, 2H), 7.23 (t, J=8.85 Hz, 2H), 7.32 (s, 1H), 7.43 (s, 1H),7.57-7.63 (m, 2H), 7.63-7.68 (m, 1H), 7.73 (s, 1H), 7.79-7.86 (m, 1H),7.99 (s, 1H), 8.09-8.16 (m, 2H). LCMS m/z 529.00 (M+H). HPLC Rt 11.771min. (Sunfire C18), 94.2% purity.

2-(4-Fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.90-1.02 (m, 6H), 1.84-2.00 (m, 1H),2.50 (s, 3H), 2.94 (d, J=4.77 Hz, 3H), 3.17-3.27 (m, 2H), 5.39 (s, 2H),7.18-7.29 (m, 2H), 7.46-7.56 (m, 3H), 7.58-7.68 (m, 2H), 7.71 (br. s.,1H), 7.79 (s, 1H), 8.00 (d, J=1.51 Hz, 1H), 8.08-8.21 (m, 2H). LCMS m/z557.11 (M+H). HPLC Rt 8.964 min. (Sunfire C18), 92.0% purity.

5-(3-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.87-1.01 (m, 6H), 1.83-1.98 (m, 1H),2.93 (d, J=4.52 Hz, 3H), 3.13-3.26 (m, 2H), 4.49 (t, J=5.14 Hz, 2H),4.61 (t, J=5.02 Hz, 2H), 7.19-7.27 (m, 2H), 7.28-7.33 (m, 1H), 7.39-7.42(m, 1H), 7.43-7.52 (m, 1H), 7.57-7.66 (m, 2H), 7.71-7.77 (m, 1H), 7.81(s, 1H), 7.96 (d, J=1.00 Hz, 1H), 8.06-8.17 (m, 3H), 8.30 (s, 1H). LCMSm/z 556.11 (M+H). HPLC Rt 7.969 min. (Sunfire C18), 92.0% purity.

5-(3-(Cyanomethoxy)-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (500 MHz, THF-d8) δ ppm 0.96 (d, J=6.71 Hz, 6H), 1.85-1.98 (m,1H), 2.85-2.98 (m, 3H), 3.16-3.27 (m, 2H), 5.11 (s, 2H), 7.18-7.29 (m,2H), 7.42-7.49 (m, 1H), 7.54 (s, 1H), 7.60-7.71 (m, 2H), 7.79-7.88 (m,2H), 8.00 (s, 1H), 8.08-8.19 (m, 2H). LCMS m/z 500.00 (M+H). HPLC Rt9.584 min. (Sunfire C18), 95.9% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)biphenyl-3-yl)-N-methylbenzofuran-3-carboxamide

To a Biotage microwave vial was added 1,4-dioxane (2.0 mL), water (200μL), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (16.42 mg,0.040 mmol),5-(3-chloro-5-(isobutylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(96 mg, 0.2 mmol), potassium phosphate tribasic (170 mg, 0.800 mmol),palladium(II) acetate (8.98 mg, 0.040 mmol), and phenylboronic acid(73.2 mg, 0.600 mmol). The vial was capped, degassed, flushed with N₂and heated in the microwave for 15 minutes at 150° C. The solvent wasremoved in a Thermo/Savant SpeedVac and the crude product was dissolvedin DMF (1.8 mL) and purified by preparative HPLC using a ShimadzuprepHPLC employing acetonitrile/water/0.1% TFA where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 30×100 mm column at a gradient of 30-100% B and a flow rate of 40mL/min. over 8 minutes with a 10 minute hold. The tubes with desiredproduct were evaporated overnight in a SAVANT/THERMO Speedvac. The LC/MSdata was obtained on a Shimadzu analytical LC/Micromass Platform LC(ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% TFA/10% HPLC grade water), (A=90% HPLC gradewater/0.1% TFA/10% HPLC grade acetonitrile), in 3 minutes with a 1minute hold at a rate of 4 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 20-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of20-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.99 (d, J=6.78 Hz, 6H),1.92-2.05 (m, 1H), 2.91-3.03 (m, 3H), 3.21-3.27 (m, 2H), 7.25 (t, J=8.78Hz, 2H), 7.36-7.42 (m, 1H), 7.49 (t, J=7.53 Hz, 2H), 7.65-7.70 (m, 1H),7.75 (d, J=8.28 Hz, 3H), 7.91-7.98 (m, 2H), 8.00 (d, J=1.51 Hz, 1H),8.03-8.10 (m, 3H). LCMS m/z 521.33 (M+H), Rt 2.715 min. HPLC (SunfireC18) Rt 11.531 min, 95% purity and (XBridge Phenyl C18) Rt 12.868 min.,92% purity.

2-(4-Fluorophenyl)-5-(4-hydroxy-3-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a 350 mL sealed tube was added2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-4-methoxyphenyl)-N-methylbenzofuran-3-carboxamide(1.14 g, 2.4 mmol), dichloroethane (250 mL) and boron tribromide-methylsulfide complex (6.0 g, 19.2 mmol). The vessel was sealed and themixture heated with stirring at 90° C. overnight. The reaction mixturewas cooled to 0° C. and 100 mL of cold methanol was added and themixture stirred for 30 minutes then evaporated to near dryness. Theaddition of methanol followed by evaporation was repeated to give a tansolid (78%). The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade acetonitrile/0.1% TFA/10% HPLC gradewater), (A=90% HPLC grade water/0.1% TFA/10% HPLC grade acetonitrile),in 3 minutes with a 1 minute hold at a rate of 4 mL/minute. HPLC puritywas determined using a Shimadzu analytical LC at 254 nm and 256 nm witha Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% TFA with a gradient of 40-100% B (B=95% HPLCgrade acetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water),(A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Gemini C18 3 μm4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonatewith a gradient of 50-100% B (B=95% HPLC grade methanol/10 mM ammoniumbicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammoniumbicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute holdat a rate of 1 mL/minute. ¹H NMR (500 MHz, THF-d8) δ ppm 0.97 (d, J=6.71Hz, 6H), 1.83-2.07 (m, 1H), 2.92 (d, J=4.88 Hz, 3H), 3.24 (t, J=6.41 Hz,2H), 6.96 (d, J=8.55 Hz, 1H), 7.23 (t, J=8.70 Hz, 2H), 7.50-7.55 (m,1H), 7.55-7.59 (m, 2H), 7.67 (dd, J=8.55, 2.14 Hz, 1H), 7.89 (s, 1H),7.99 (d, J=2.14 Hz, 1H), 8.09 (dd, J=8.70, 5.34 Hz, 2H), 8.35 (br. s.,1H). LCMS m/z 461.18 (M+H), Rt 2.613 min. HPLC (Sunfire C18) Rt 10.033min., 100% purity and (Gemini C18) Rt 9.748 min., 100% purity.

2-(4-Fluorophenyl)-N-methyl-5-(5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-2-(trifluoromethyl)phenyl)benzofuran-3-carboxamide

To a Biotage microwave vial was added2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(39.5 mg, 0.1 mmol), dioxane (2 mL), water (0.200 mL),3-chloro-N-(1-(pyridin-2-yl)cyclopropyl)-4-(trifluoromethyl)benzamide(37.5 mg, 0.110 mmol) (prepared from the coupling of3-chloro-4-(trifluoromethyl)benzoic acid with1-(pyridin-2-yl)cyclopropanamine dihydrochloride using HATU andN,N-Diisopropylethylamine in DMF at r.t.),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos, 8.21 mg,0.020 mmol), tribasic potassium phosphate, (85 mg, 0.400 mmol) andfinally palladium(II) acetate (4.49 mg, 0.020 mmol). The vial was cappedand subjected to microwave heating (100° C.) for 10 minutes. Aftercooling the reaction mixture, the solvent was removed and the crudeproduct was purified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25mL/min. over 20 minutes with a 5 minute hold. The solvent was removedyielding 11.2 mgs (20% yield) of the desired pyridylcarboxamide as ayellow solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLCgrade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLCgrade methanol), in 4 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a GeminiC18 3.0 μm 4.6×150 mm column employing water/methanol/10 mM ammoniumbicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm1.22-1.33 (m, 2H), 1.63-1.69 (m, 2H), 2.87 (d, J=4.77 Hz, 3H), 7.03 (dd,J=7.40, 4.89 Hz, 1H), 7.23 (t, J=8.66 Hz, 2H), 7.33 (d, J=8.28 Hz, 1H),7.40 (d, J=7.53 Hz, 2H), 7.52-7.63 (m, 2H), 7.73 (d, J=1.25 Hz, 1H),7.90 (d, J=8.03 Hz, 1H), 7.97 (s, 1H), 8.05-8.16 (m, 3H), 8.40 (d,J=4.77 Hz, 1H), 8.69 (s, 1H). LCMS Rt=2.193 min., m/z 574.3 (M+H). HPLCRt=7.435 min. (Sunfire C18), 97.5% purity and 11.823 min. (Gemini C18),100% purity.

2-(4-Fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-(morpholin-2-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide, TFA

To a 2 dram vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(isobutylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(46.0 mg, 0.1 mmol), DMF (2 mL), 4.0 equivalents (60 μL, 0.400 mmol) ofDBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.4 mmol) and 4.0 equivalentsof tert-butyl 2-(2-bromoethyl)morpholine-4-carboxylate (236 mg, 0.400mmol). The vial was capped and the reaction mixture heated for eighteenhours at 85° C. The crude product was purified using a Shimadzupreparative HPLC employing acetonitrile/water/trifluoroacetic acid wheresolvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid witha Waters Sunfire 5 μm C18 19×150 mm column at a gradient of 20-100% Band a flow rate of 25 mL/min. over 20 minutes with a 10 minute hold. Thesolvent mixture was removed on the rotovap and the resulting white solid(19.2 mgs) was taken up in 2 mL of dichloroethane containing 200 uL oftrifluoroacetic acid. The acid mixture was stirred for 60 minutes. Thevolatiles were then removed, the process repeated again giving 20 mgs(29% yield, 2 steps) of2-(4-fluorophenyl)-5-(5-(isobutylcarbamoyl)-2-(2-(morpholin-2-yl)ethoxy)phenyl)-N-methylbenzofuran-3-carboxamide,TFA as a white solid. The NMR spectrum was recorded at room temperatureusing a Bruker DRX400 spectrometer. The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column,with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1minute hold at a rate of 0.8 mL/minute. HPLC purity was determined usinga Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1%trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLCgrade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC puritywas then confirmed with an orthogonal solvent system and column using aShimadzu analytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150mm column employing water/methanol/10 mM ammonium bicarbonate with agradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammoniumbicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammoniumbicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute holdat a rate of 1 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 0.93 (d, J=6.53Hz, 6H), 1.87 (m, 3H), 2.90 (d, J=4.77 Hz, 3H), 3.08-3.12 (m, 2H),3.16-3.20 (m, 2H), 3.31 (d, J=9.54 Hz, 2H), 3.95-4.11 (m, 3H), 4.23-4.31(m, 1H), 4.35 (br. s., 1H), 7.08 (d, J=8.78 Hz, 1H), 7.25 (t, J=8.66 Hz,2 H), 7.45 (dd, J=8.53, 1.76 Hz, 1H), 7.54 (t, J=5.65 Hz, 1H), 7.62 (d,J=8.53 Hz, 1H), 7.84 (dd, J=8.53, 2.26 Hz, 1H), 7.88 (d, J=2.01 Hz, 1H),7.91 (d, J=4.02 Hz, 1H), 7.98-8.07 (m, 3H). LCMS m/z 574.5 (M+H),Rt=2.390 min. HPLC (Sunfire C18) Rt=6.870 min., 99.3% purity and(XBridge Phenyl C18) Rt=10.973 min., 99.2% purity.

tert-Butyl 2-(2-bromoethyl)morpholine-4-carboxylate

To a 25 mL round-bottomed flask was added 2-(morpholin-2-yl)ethanol (100mg, 0.762 mmol), DCM (1 mL), and triethylamine (0.106 mL, 0.762 mmol).Di-tert-butyl dicarbonate (0.177 mL, 0.762 mmol) in DCM (1 mL) was thenadded dropwise via syringe. The mixture was stirred at room temperatureunder nitrogen for 3 hours. Volatiles were removed and NMR was taken ofthe colorless oil (176 mgs, 100% yield, 96% purity). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.39 (s, 9H), 1.47-1.61 (m, 2H), 2.83 (br. s., 1H),3.28-3.42 (m, 3H), 3.46 (q, J=6.10 Hz, 2H), 3.68 (d, J=11.29 Hz, 1H),3.76 (d, J=10.38 Hz, 2H), 4.45 (t, J=5.04 Hz, 1H).

To a 25 mL round-bottomed flask at 0° C. was added tert-butyl2-(2-hydroxyethyl)morpholine-4-carboxylate (0.176 g, 0.762 mmol), DCM (4mL), 1H-imidazole (0.104 g, 1.524 mmol), perbromomethane (0.379 g, 1.143mmol), and triphenylphoshphine (0.190 g, 0.723 mmol). The mixture wasstirred overnight slowly reaching room temperature. The yellow solutionwas further diluted with 50 mL of DCM, washed with water, brine, driedover sodium sulfate, and filtered. The crude product was then pushedthrough a plug of silica gel and the solvent was removed to give 213 mgsof a light yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H),1.94 (q, J=6.86 Hz, 1H), 2.56-2.66 (m, 1H), 2.76-2.91 (m, 1 H),3.35-3.47 (m, 4H), 3.50-3.61 (m, 1H), 3.68 (br. s., 1H), 3.74-3.86 (m,2H).

5-(2-(2-(Dimethylamino)ethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,TFA

To a small microwave vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-phenylcyclopropycarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (11.3 mgs, 0.022mmol) (obtained from the de-methylation of the methoxy precursor usingBoron tribromide-methyl sulfide complex (1,2-dichloroethane, 90° C.)),dioxane (2 mL), triphenylphosphine (105 mg, 0.400 mmol),2-(dimethylamino)ethanol (0.025 mL, 0.250 mmol), and di-tert-butylazodicarboxylate (69.1 mg, 0.300 mmol). The vial was crimped and thereaction mixture subjected to microwave heating (140° C.) for 20 minutesin a Biotage Initiator. The solvent was removed under a stream ofnitrogen, the crude product taken up in 2 mL of acetonitrile andpurified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Sunfire 5 μm C1819×150 mm column at a gradient of 20-100% B and a flow rate of 20mL/min. over 20 minutes with a 5 minute hold. The solvent was removed togive 14.5 mgs (90% yield) of5-(2-(2-(dimethylamino)ethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,TFA salt as a white solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade methanol/0.1% TFA/10% HPLC grade water),(A=90% HPLC grade water/0.1% TFA/10% HPLC grade methanol), in 4 minuteswith a 1 minute hold at a rate of 4 mL/minute. HPLC purity wasdetermined using a Shimadzu analytical LC at 254 nm and 256 nm with aWaters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% trifluoroacetic ac with a gradient of 10-100% B(B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a Gemini C18 3.0μm 4.6×150 mm column employing water/methanol/10 mM ammonium bicarbonatewith a gradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammoniumbicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammoniumbicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute holdat a rate of 1 mL/minute. The NMR spectrum was recorded at roomtemperature using a Bruker DRX400 spectrometer. Chemical shifts werereported in ppm relative to the deuterated solvent used. Couplingconstants were reported in hertz. Peak multiplicity was reported usingthe following abbreviations: s (singlet), d (doublet), dd (doublet ofdoublets), t (triplet), m (multiplet), br (broad). ¹H NMR (400 MHz,THF-d8) δ ppm 1.22-1.27 (m, 2H), 1.28-1.33 (m, 2H), 2.70 (s, 6H), 2.90(d, J=4.52 Hz, 3H), 3.41-3.46 (m, 2H), 4.47-4.53 (m, 2H), 7.06-7.12 (m,1H), 7.14-7.27 (m, 5H), 7.28-7.35 (m, 2H), 7.47 (dd, J=8.53, 1.76 Hz,1H), 7.54-7.61 (m, 2H), 7.89 (dd, J=8.53, 2.26 Hz, 1H), 7.94 (dd,J=4.02, 2.01 Hz, 2H), 8.03-8.10 (m, 2H), 8.28 (s, 1H). LCMS m/z 592.4(M+H), Rt=2.065 min. HPLC Rt=7.025 min. (Sunfire C18), 95.2% purity and11.979 min. (Gemini C18), 95.7% purity.

5-(2-(2-(Dimethylamino)ethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, TFA

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of 0-100% B (B=90%HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water),(A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grademethanol), in 4 minutes with a 1 minute hold at a rate of 0.8 mL/minute.HPLC purity was determined using a Shimadzu analytical LC at 254 nm and256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100%B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a PhenomenexGemini C18 3.0 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 1.32-1.37 (m, 2H), 1.59-1.65 (m, 2H), 2.77 (s, 6H), 2.90(d, J=4.77 Hz, 3H), 3.47-3.54 (m, 2H), 4.48-4.55 (m, 2H), 7.17 (d,J=8.53 Hz, 1H), 7.20-7.27 (m, 2H), 7.31 (dd, J=6.90, 5.65 Hz, 1H),7.49-7.59 (m, 2H), 7.61-7.70 (m, 2 H), 7.86 (td, J=7.78, 1.51 Hz, 1H),7.94 (dd, J=8.53, 2.26 Hz, 1H), 7.97 (d, J=1.00 Hz, 1H), 7.99-8.09 (m,3H), 8.54 (d, J=4.27 Hz, 1H), 9.07 (s, 1H). LCMS Rt=2.412 min., m/z593.4 (M+H). HPLC Rt=5.185 min. (Sunfire C18), 96.4% purity and 11.558min. (Gemini C18), 98.2% purity.

2-(4-Fluorophenyl)-5-(2-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex-Luna 10 nM C18, 3.0×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grademethanol), in 4 minutes with a 1 minute hold at a rate of 5 mL/minute.HPLC purity was determined using a Shimadzu analytical LC at 254 nm and256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm column employingwater/acetonitrile/0.1% trifluoroacetic acid with a gradient of 10-100%B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5% HPLC gradewater), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5% HPLC gradeacetonitrile), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. The HPLC purity was then confirmed with an orthogonal solventsystem and column using a Shimadzu analytical LC with a PhenomenexGemini C18 3.0 μm 4.6×150 mm column employing water/methanol/10 mMammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.31-1.40 (m, 2H), 1.56-1.65 (m, 2H), 2.82 (d, J=4.52 Hz,3H), 3.85 (s, 3H), 7.24 (d, J=8.53 Hz, 1H), 7.30 (dd, J=6.78, 5.52 Hz,1H), 7.39 (t, J=8.91 Hz, 2H), 7.46 (d, J=8.03 Hz, 1H), 7.52 (dd, J=8.53,1.76 Hz, 1H), 7.68-7.75 (m, 2H), 7.86 (s, 1H), 7.93-8.02 (m, 4H), 8.45(d, J=4.52 Hz, 1H), 8.49 (d, J=4.27 Hz, 1H), 9.23 (s, 1H). LCMS Rt=2.557min., m/z 536.10 (M+H). HPLC Rt=6.683 min. (Sunfire C18), 96.3% purityand 11.493 min. (Gemini C18), 99.5% purity.

2-(4-Fluorophenyl)-5-(2-hydroxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a 100 mL round-bottomed flask equipped with a reflux condenser wasadded2-(4-fluorophenyl)-5-(2-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(400 mg, 0.747 mmol), DCE (42 mL) and boron tribromide-methyl sulfidecomplex (1868 mg, 5.97 mmol). The solution was placed under nitrogen andstirred overnight at 90° C. The reaction mixture was cooled to roomtemperature, quenched with methanol and evaporated to near dryness. Themixture was taken up in 10 mL of methanol and purified using a Shimadzupreparative HPLC employing methanol/water/0.1% trifluoroacetic acidwhere solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with aPhenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 40-100% Band a flow rate of 40 mL/min. over 10 minutes with a 5 minute hold. Thesolvent was evaporated giving 234 mgs (60% yield) of2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideas a white solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradient of0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLCgrade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLCgrade methanol), in 4 minutes with a 1 minute hold at a rate of 4mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 1.25-1.31 (m, 2H), 1.59-1.66(m, 2H), 2.90 (d, J=4.52 Hz, 3H), 6.91 (d, J=8.53 Hz, 1H), 7.08 (dd,J=6.90, 5.40 Hz, 1H), 7.17-7.24 (m, 2H), 7.45-7.65 (m, 5H), 7.79 (dd,J=8.41, 2.13 Hz, 1H), 7.88 (d, J=1.25 Hz, 1H), 7.93 (d, J=2.01 Hz, 1H),8.08-8.17 (m, 2H), 8.39-8.45 (m, 1H), 8.49 (br. s., 1H). LCMS Rt=1.495min., m/z 522.33 (M+H), 94% purity.

2-(4-Fluorophenyl)-5-(2-(2-hydroxyethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a small screw cap vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (19.5 mg, 0.037 mmol)in DMF (1.3 mL), (2-bromoethoxy)(tert-butyl)dimethylsilane (0.024 mL,0.112 mmol), and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 0.023 mL,0.150 mmol). The vial was capped and shaken at 80° C. for 18 hours. TheDMF was removed under a stream of nitrogen to give5-(2-(2-(tert-butyldimethylsilyloxy)ethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide asa tan oil. To the mixture was then added 1.3 mL of tetrahydrofuran alongwith 2 eq. of 1 M HCl (0.075 mL, 0.075 mmol). The solution was stirredfor 1 hour at room temperature. The reaction mixture was transferred toa separatory funnel, diluted with ethyl acetate, washed sequentiallywith sodium bicarbonate, brine and dried over magnesium sulfate. Theproduct mixture was filtered and the solvent was evaporated. The crudeproduct was taken up in 1.8 mL of acetonitrile and 200 μL of DMF andpurified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Sunfire C1819×150 mm column at a gradient of 20-100% B and a flow rate of 20mL/min. over 20 minutes with a 5 minute hold. 15.2 mgs of2-(4-fluorophenyl)-5-(2-(2-hydroxyethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methyl benzofuran-3-carboxamide (70% yield, 2 steps)was obtained after solvent evaporation. The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with agradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade methanol), in 4 minutes with a 1 minute hold at arate of 4 mL/minute. HPLC purity was determined using a Shimadzuanalytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acidwith a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Gemini C18 3.0 μm 4.6×150 mm column employingwater/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B(B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC gradewater), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grademethanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.¹H NMR (400 MHz, THF-d8) δ ppm 1.20-1.27 (m, 2H), 1.28-1.36 (m, 2H),2.87-2.96 (m, 3H), 3.75-3.83 (m, 3H), 4.10 (t, J=4.89 Hz, 2H), 7.04-7.13(m, 2H), 7.16-7.25 (m, 4H), 7.29-7.35 (m, 2H), 7.43 (d, J=4.27 Hz, 1H),7.51-7.59 (m, 2 H), 7.87 (dd, J=8.53, 2.26 Hz, 1H), 7.94 (d, J=2.26 Hz,1H), 8.02 (s, 1H), 8.11-8.18 (m, 2H), 8.25 (s, 1H). LCMS Rt=2.671 min.,m/z 565.3 (M+H). HPLC Rt=9.454 min. (Sunfire C18), 95.0% purity and11.611 min. (Gemini C18), 99.7% purity.

2-(4-Fluorophenyl)-5-(2-(2-hydroxyethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 mm 4 6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersXBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 1.23-1.29 (m, 2H), 1.62-1.68 (m, 2H), 2.91 (d, J=4.77 Hz,3H), 3.80 (t, J=4.77 Hz, 2 H), 4.13 (t, J=4.89 Hz, 2H), 6.99 (m, 1H),7.14 (d, J=8.53 Hz, 1H), 7.17-7.25 (m, 2H), 7.37-7.47 (m, 2H), 7.49-7.61(m, 3H), 7.93 (dd, J=8.53, 2.26 Hz, 1H), 8.00 (d, J=2.26 Hz, 1H),8.03-8.06 (m, 1H), 8.11-8.18 (m, 2H), 8.33 (s, 1H), 8.35-8.41 (m, 1H).LCMS m/z 566.4 (M+H), Rt=2.038 min. HPLC (Sunfire C18) Rt=5.916 min.,100% purity and (XBridge Phenyl C18) Rt=10.474 min., 100% purity.

5-(2-(2-Amino-2-oxoethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a small screw cap vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide (15.6 mg, 0.030 mmol)in DMF (2 mL), 2-bromoacetamide (41.4 mg, 0.300 mmol), and DBU(1,8-diazabicyclo[5.4.0]undec-7-ene, 0.060 mL, 0.400 mmol). The vial wascapped and shaken at 75° C. overnight. The crude reaction mixture wascooled, evaporated, taken up in 2 mL of acetonitrile and purified usinga Shimadzu preparative HPLC employing acetonitrile/water/trifluoroaceticacid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroaceticacid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroaceticacid with a Xterra C18 19×100 mm column at a gradient of 25-100% B and aflow rate of 25 mL/min. over 12 minutes with a 8 minute hold. Thesolvent was evaporated overnight giving 9.9 mgs (54.9% yield) ofcarboxamide as a white solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of4 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a GeminiC18 3.0 μm 4.6×150 mm column employing water/methanol/10 mM ammoniumbicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm1.21-1.26 (m, 2H), 1.26-1.33 (m, 2H), 2.87-2.92 (m, 3H), 4.47 (s, 2H),7.05-7.13 (m, 2H), 7.15-7.25 (m, 4 H), 7.27-7.34 (m, 2H), 7.45-7.51 (m,1H), 7.52-7.61 (m, 2H), 7.84-7.92 (m, 2 H), 7.93-8.00 (m, 2H), 8.09-8.20(m, 3H), 8.29 (s, 1H). LCMS Rt=2.522 min., m/z 578.3 (M+H). HPLCRt=8.693 min. (Sunfire C18), 91.0% purity and 11.423 min. (Gemini C18),92% purity.

5-(2-(2-Amino-2-oxoethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with aPhenomenex Gemini C18 3.0 μm 4.6×150 mm column employingwater/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B(B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC gradewater), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grademethanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.¹H NMR (400 MHz, THF-d8) δ ppm 1.25-1.37 (m, 2 H), 1.57-1.67 (m, 2H),2.88-2.96 (m, 3H), 4.49 (s, 2H), 6.51 (br. s., 1H), 6.79 (br. s., 1H),7.10 (d, J=8.78 Hz, 1H), 7.17-7.27 (m, 3H), 7.52-7.66 (m, 4H), 7.72-7.82(m, 1H), 7.94 (dd, J=8.53, 2.26 Hz, 1H), 7.99 (s, 1H), 8.03 (d, J=2.26Hz, 1H), 8.08-8.18 (m, 2H), 8.50 (d, J=4.27 Hz, 1H), 8.91 (br. s., 1H).LCMS Rt=2.578 min., m/z 580.3 (M+2H). HPLC Rt=9.368 min. (Sunfire C18),96.0% purity and 10.756 min. (Gemini C18), 97.9% purity.

5-(2-(2-Aminoethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, TFA

To a 2 dram vial was added2-(4-fluorophenyl)-5-(2-hydroxy-5-(1-phenylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(40.2 mg, 0.078 mmol) in 3 mL of DMF along with 3 eq. of2-(2-bromoethyl)isoindoline-1,3-dione (58.8 mg, 0.232 mmol) and 4 eq. ofDBU (1,8-diaza bicyclo[5.4.0]undec-7-ene, 0.046 mL, 0.308 mmol). Thevial was capped and shaken at 75° C. over night. The crude reactionmixture was evaporated, taken up in 2 mL of acetonitrile and purifiedusing a Shimadzu preparative HPLC employing acetonitrile/water/0.1%trifluoroacetic acid where solvent A was 10% acetonitrile/90% water/0.1%trifluoroacetic acid and solvent B was 10% water/90% acetonitrile/0.1%trifluoroacetic acid with a Xterra C18 19×100 mm column at a gradient of25-100% B and a flow rate of 25 mL/min. over 12 minutes with a 8 minutehold. The solvent was evaporated yielding 10.7 mgs of the phthalimideintermediate as a white solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 4mL/minute. LCMS m/z 694.4 (M+H), Rt=3.128 min., 93.7% purity. To a smallscrew cap vial was added the phthalimide intermediate,5-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-5-(1-phenylcyclo-propylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(10.7 mg, 0.015 mmol) in 2 mL of methanol and anhydrous hydrazine (0.780μL, 0.025 mmol). The vial was placed in a pre-equilibrated oil bath setto 75° C. and the solution refluxed for 90 minutes. The product wascooled to room temperature and the solvent was evaporated. The resultingoil was diluted with 10 mL of DCM, washed with 1 mL of 0.5M NaOH andextracted. The solvent was evaporated and the crude product was taken upin 1.8 mL of acetonitrile and 200 μL of DMF and purified using aShimadzu preparative HPLC employing acetonitrile/water/trifluoroaceticacid where solvent A was 10% acetonitrile/90% water/0.1% trifluoroaceticacid and solvent B was 10% water/90% acetonitrile/0.1% trifluoroaceticacid with a Sunfire C18 19×150 mm column at a gradient of 20-100% B anda flow rate of 20 mL/min. over 20 minutes with a 5 minute hold. Thesolvent was evaporated giving 7.0 mgs (14% yield, 2 steps) of5-(2-(2-aminoethoxy)-5-(1-phenylcyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,TFA as a white solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Sunfire 5 μm C18, 4.6×50 mm column, with a gradientof 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade methanol), in 4 minutes with a 1 minute hold at a rate of 4mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a GeminiC18 3.0 μm 4.6×150 mm column employing water/methanol/10 mM ammoniumbicarbonate with a gradient of 10-100% B (B=95% HPLC grade methanol/10mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10mM ammonium bicarbonate/5% HPLC grade methanol), in 10 minutes with a 10minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm1.21-1.27 (m, 2H), 1.28-1.35 (m, 2H), 2.89 (d, J=4.77 Hz, 3H), 3.39 (t,J=4.77 Hz, 2H), 4.38 (t, J=5.02 Hz, 2H), 7.05-7.13 (m, 1H), 7.16-7.28(m, 5 H), 7.29-7.35 (m, 2H), 7.49-7.60 (m, 2H), 7.62 (br. s., 1H), 7.87(dd, J=8.53, 2.26 Hz, 1H), 7.96-8.05 (m, 3H), 8.07 (d, J=1.00 Hz, 1H),8.30 (s, 1H). LCMS Rt=2.023 min., m/z 564.3 (M+H). HPLC Rt=6.931 min.(Sunfire C18), 100% purity and 11.423 min. (Gemini C18), 98.9% purity.

5-(2-(2-Aminoethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,2 TFA

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8mL/minute. HPLC purity was determined using a Shimadzu analytical LC at254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersXBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 1.23-1.33 (m, 2 H), 1.60-1.67 (m, 2H), 2.89 (d, J=4.77 Hz,3H), 3.41 (t, J=5.14 Hz, 2H), 4.40 (t, J=5.14 Hz, 2H), 6.58 (br. s.,2H), 7.01-7.11 (m, 1H), 7.16-7.29 (m, 3H), 7.46 (d, J=8.03 Hz, 1H),7.52-7.70 (m, 4H), 7.93 (dd, J=8.53, 2.26 Hz, 1H), 7.98-8.05 (m, 3H),8.07 (s, 1H), 8.41 (d, J=4.77 Hz, 1H), 8.56 (s, 1H). LCMS m/z 565.4(M+H), Rt=1.628 min. HPLC (Sunfire C18) Rt=5.048 min., 99.9% purity and(XBridge Phenyl C18) Rt=10.531 min., 100% purity.

5-Bromo-2,4-dimethoxy-N-(1-(pyridin-2-yl)cyclopropyl)benzamide

To a 250 mL round-bottomed flask was added chloroform (60 mL) along with2,4-dimethoxybenzoic acid (2.0 g, 10.98 mmol). The solution was cooledto 0° C. and bromine (0.566 mL, 10.98 mmol) was added dropwise over 5minutes. The solution was allowed to warm to room temperature andstirred overnight. The resulting solid was filtered, washed with coldchloroform and dried under vacuum to give 2.49 g (8.6 mmol, 78% yield)of 5-bromo-2,4-dimethoxybenzoic acid as a yellow solid. The LC/MS datawas obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at220 nm using the following set of conditions: Phenomenex Luna 3 μm C18,2×30 mm column, with a gradient of 0-100% B (B=90% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90%HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile),in 2 minutes with a 1 minute hold at a rate of 1.0 mL/minute. ¹H NMR(400 MHz, DMSO-d6) δ ppm 3.88 (s, 3H), 3.95 (s, 3H), 6.78 (s, 1H), 7.86(s, 1H). LCMS Rt=1.453 min., m/z 262.99 (M+H), 93% purity.

To a 2 dram vial was added 5-bromo-2,4-dimethoxybenzoic acid (1.044 g, 4mmol), DMF (48.2 mL), N,N-Diisopropylethylamine (2.79 mL, 16.00 mmol),1-(pyridin-2-yl)cyclopropanamine, 2HCl (0.911 g, 4.40 mmol), and finallyHATU (2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V), 6.08 g, 16.00 mmol). The vial wascapped and shaken for 16 hours at room temperature. The crude reactionmixture was diluted with 10 mL of DCM, washed with 5 mL of 1M HCl,extracted, washed with 20 mL of brine, and dried over magnesium sulfate.The solution was pushed through a plug of silica gel and evaporated todryness. Trituration with 20 mL of diethyl ether gave 1.6 grams of5-bromo-2,4-dimethoxy-N-(1-(pyridin-2-yl)cyclopropyl)benzamide as a tansolid (76% yield). ¹H NMR (400 MHz, THF-d8) δ ppm 1.22-1.32 (m, 2H),1.59-1.67 (m, 2H), 3.94 (s, 3H), 4.02 (s, 3H), 6.72 (s, 1H), 7.09 (m,1H), 7.47 (d, J=8.03 Hz, 1H), 7.62 (td, J=7.72, 1.88 Hz, 1H), 8.20 (s,1H), 8.39-8.52 (m, 2H). LCMS Rt=2.162 min., m/z 379.2 (M+2H), 96%purity.

5-Bromo-2-methoxy-4-methylbenzoic acid

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B(B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grademethanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute.Yellow solid, 63.5% yield. LCMS Rt=1.545 min., m/z 246.99 (M+H), 90%purity. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21-2.44 (m, 3H), 3.82 (s, 3H),7.17 (s, 1H), 7.78 (s, 1H), 12.72 (br. s., 1H).

5-Bromo-2-methoxy-4-methyl-N-(1-(pyridin-2-yl)cyclopropyl)benzamide

The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Phenomenex Luna 3 μm C18, 2.0×50 mm column, with a gradient of 0-100% B(B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC gradeacetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8mL/minute. Tan solid, 68% yield, 100% purity. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.34-1.42 (m, 2H), 1.58-1.66 (m, 2H), 2.39 (s, 3H), 3.96 (s, 3H),7.05 (s, 1H), 7.40 (dd, J=6.90, 5.90 Hz, 1H), 7.76 (d, J=8.03 Hz, 1H),7.97 (td, J=7.78, 1.76 Hz, 1H), 8.10 (s, 1H), 8.60 (d, J=5.27 Hz, 1H),8.88 (s, 1H). LCMS Rt=3.525 min., m/z 362.88 (M+H), 98% purity.

Methyl 4-hydroxy-2-methoxybenzoate

To a 250 mL Erlenmeyer flask was added methyl 4-amino-2-methoxybenzoate(7.5 g, 41.4 mmol) and a 25% solution of sulfuric acid (40 mL, 188mmol). The solution was cooled to 0° C. and a saturated solution ofsodium nitrite (4.29 g, 62.2 mmol) was added drop wise. The orangemixture was stirred for 15 minutes. The resulting diazonium solution wasthen very slowly poured into a 1 L flask containing 500 mL of 3%sulfuric acid. The solution was stirred for 5 minutes then transferredto a separatory funnel. The reaction mixture was diluted with 150 mL ofDCM, extracted, dried over magnesium sulfate and concentrated. to a redsolid. The resulting solid was triturated with hexane to give 5.71 gramsof the desired phenol as a red powder (73% yield). The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: Waters Sunfire 5 μm C18,4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grademethanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLCgrade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2minutes with a 1 minute hold at a rate of 4 mL/minute. ¹H NMR (400 MHz,DMSO-d6) δ ppm 3.67-3.72 (m, 3 H), 3.74 (s, 3H), 6.39 (dd, J=8.66, 2.13Hz, 1H), 6.45 (d, J=2.13 Hz, 1H), 7.59 (d, J=8.66 Hz, 1H). LCMS Rt=1.070min., m/z 183.09 (M+H), 96% purity.

Methyl 4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate

To a sealed tube was added 2-bromoacetamide (2.272 g, 16.47 mmol), DMF(50 mL), cesium carbonate (7.15 g, 21.96 mmol) and methyl4-hydroxy-2-methoxybenzoate (1.00 g, 5.49 mmol). The tube was sealed andheated for 16 hours at 85° C. The reaction mixture was diluted with DCM,washed sequentially with 10 mL of 1M HCl, water, and brine. The solutionwas dried over sodium sulfate, filtered and the solvent removed to give1.2 grams of methyl 4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (78%yield) as a yellow powder. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with agradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at arate of 4 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 3.71-3.76 (m, 3H),3.80-3.84 (m, 3H), 4.45 (s, 2H), 6.56 (dd, J=8.66, 2.38 Hz, 1H), 6.65(d, J=2.26 Hz, 1H), 6.77 (br. s., 1H), 6.92 (br. s., 1H), 7.75 (d,J=8.78 Hz, 1H). LCMS Rt=1.385 min., m/z 240.2 (M+H), 92% purity.

To a 250 mL round-bottomed flask was added methyl4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (1.2 g, 5.14 mmol) andchloroform (40 mL). The mixture was placed under a nitrogen atmosphereand cooled to 0° C. Bromine (0.263 mL, 5.14 mmol) was added drop wise(in 3 mL of chloroform) and the solution was allowed to warm to roomtemperature overnight. The orange solid was cooled with an ice bath,filtered, washed sequentially with cold chloroform, then diethyl ether.The product was dried under vacuum giving 1.7 grams (91% yield) ofmethyl 4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate as an orangesolid. The LC/MS data was obtained on a Shimadzu analytical LC/MicromassPlatform LC (ESI+) at 220 nm using the following set of conditions:Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B(B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC gradewater), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grademethanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute.¹H NMR (400 MHz, THF-d8) δ ppm 3.76 (s, 3H), 3.88 (s, 3H), 4.63 (s, 2H),6.76 (s, 1H), 7.10 (br. s., 2H), 7.96 (s, 1H). LCMS Rt=1.793 min., m/z319.1 (M+H), 90% purity.

5-(2,4-Dimethoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a microwave vial was added5-bromo-2,4-dimethoxy-N-(1-(pyridin-2-yl)cyclopropyl)benzamide (41.5 mg,0.110 mmol),2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(39.5 mg, 0.1 mmol), dioxane (2.00 mL), water (0.200 mL),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos, 8.21 mg,0.020 mmol), tribasic potassium phosphate (85 mg, 0.400 mmol) andpalladium(II) acetate (4.49 mg, 0.020 mmol). The solvent was removed andthe crude reaction mixture was taken up in 2 mL of acetonitrile andpurified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire3.5 μm C18 4.6×150 mm column at a gradient of 20-100% B and a flow rateof 25 mL/min. over 20 minutes with a 10 minute hold. The solvent wasevaporated giving 18.1 mgs (30.4% yield) of the desiredpyridylcarboxamide as a yellow solid. The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Phenomenex Luna 10 μm C18, 3.0×50 mmcolumn, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade methanol), in 4 minutes with a 1minute hold at a rate of 5 mL/minute. HPLC purity was determined using aShimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1%trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLCgrade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC puritywas then confirmed with an orthogonal solvent system and column using aShimadzu analytical LC with a Phenomenex Gemini C18 3.0 μm 4.6×150 mmcolumn employing water/methanol/10 mM ammonium bicarbonate with agradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammoniumbicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammoniumbicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute holdat a rate of 1 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 1.26-1.37 (m, 2H), 1.60-1.67 (m, 2H), 2.89 (d, J=4.77 Hz, 3H), 3.87 (s, 3H), 4.07 (s,3H), 6.78 (s, 1H), 7.10-7.23 (m, 3H), 7.39-7.44 (m, 1H), 7.46-7.52 (m,2H), 7.57 (d, J=7.78 Hz, 1H), 7.68 (td, J=7.72, 1.63 Hz, 1H), 7.74 (d,J=1.25 Hz, 1H), 8.09 (s, 1 H), 8.11-8.19 (m, 2H), 8.47 (d, J=4.52 Hz,1H), 8.59 (s, 1H). LCMS m/z 566.2 (M+H), Rt=2.608 min. HPLC (SunfireC18) Rt=6.816 min, 93.9% purity and (Gemini C18) Rt=11.676 min., 95.8%purity.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Alternative synthesis. To a sealed tube was added5-bromo-2-methoxy-4-methyl-N-(1-(pyridin-2-yl)cyclopropyl)benzamide(1.9024 g, 5.27 mmol), dioxane (70 mL),2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(2.529 g, 6.40 mmol), cesium carbonate (2.57 g, 7.90 mmol), water (14.00mL) and finally tetrakis(triphenylphosphine)palladium(0) (0.304 g, 0.263mmol). The vessel was sealed and heated for 16 hours at 85° C. in an oilbath. The mixture was cooled to room temperature, diluted with 20 ml ofDCM and pushed through a plug of celite. The resulting dark solution wasconcentrated to a grey oil. To this residue was added 20 ml of 0.5N HCl,followed by 20 ml of water. The flask was cooled in an ice bath for 30minutes and the resulting solids were collected by filtration and washedwith 10 ml of water and dried under vacuum. The crude product was takenup in 1:1 ethyl acetate/hexane and pushed through a plug of silica gel.Solvent was removed giving 1.65 grams of the product as a light tansolid.

Methyl4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoate

To a sealed tube was added methyl4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate (318 mg, 1.0 mmol),dioxane (30 mL), water (6.00 mL),2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide(593 mg, 1.500 mmol), cesium carbonate (489 mg, 1.500 mmol), andtetrakis(triphenylphosphine)palladium(0) (23.11 mg, 0.020 mmol). Thevessel was sealed and the mixture heated overnight at 85° C. Thereaction mixture was cooled, diluted with 200 mL of DCM, washedsequentially with 50 mL of 1M HCl then brine. The product was extractedand the resulting yellow solution was evaporated to dryness. The aqueouslayers were combined, cooled for 5 minutes in an ice bath and the solidsthat formed were filtered and dried under vacuum. The solids were thencombined and triturated sequentially with diethyl ether then ice coldacetonitrile (10 mL each) giving 171.6 mgs (30% yield) of methyl4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoateas a white solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersPhenyl XBridge C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,CD₃OD) δ ppm 3.04 (s, 3H), 3.92 (s, 3H), 4.03 (s, 3H), 4.71 (s, 2H),6.85 (s, 1H), 7.33 (t, J=8.78 Hz, 2H), 7.57-7.64 (m, 1H), 7.66-7.73 (m,1H), 7.87 (s, 1H), 7.96 (s, 1H), 8.00-8.08 (m, 2H). LCMS m/z 507.3(M+H), Rt=2.635 min. HPLC Rt=8.193 min. (Sunfire C18), 100% purity andRt=10.678 min. (Phenyl XBridge C18), 100% purity.

4-(2-Amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid

To a 50 mL round-bottomed flask was added methyl4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoate (171.6 mg, 0.295 mmol) in a1:1 mixture of methanol (7 mL) and THF (7 mL). To this solution was thenadded 4 eq. of 1M aqueous sodium hydroxide (1.2 mL, 1.2 mmol). Thereaction mixture was stirred overnight at room temperature. Solvent wasremoved and the crude product was diluted with 50 mL of 1:1 DCM/ethylacetate, washed sequentially with 10 mL of 1M HCl then brine. Theproduct solution was dried over sodium sulfate, filtered and evaporatedto dryness. The aqueous layers were combined, cooled in an ice bath andthe product that formed on the sides of the flask were filtered anddried under vacuum. The solids were combined, taken up in 10 mL of DMFand purified using a Shimadzu preparative HPLC employingmethanol/water/trifluoroacetic acid where solvent A was 10% methanol/90%water/0.1% trifluoroacetic acid and solvent B was 10% water/90%methanol/0.1% trifluoroacetic acid with a Phenomenex-Luna 10 μm C1830×100 mm column at a gradient of 40-100% B and a flow rate of 40mL/min. over 12 minutes with a 10 minute hold. Solvent was removedgiving 87 mgs (60% yield) of4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoicacid as a white powder. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with agradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at arate of 4 mL/minute. HPLC purity was determined using a Shimadzuanalytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acidwith a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, DMF-d7) δ ppm 2.97 (d, J=4.52 Hz, 3H), 4.02(s, 3H), 4.79 (s, 2H), 6.97 (s, 1H), 7.31 (br. s., 1H), 7.38-7.46 (m,2H), 7.51 (br. s., 1H), 7.67-7.77 (m, 2H), 7.92 (s, 1H), 7.95 (s, 1H),8.09-8.16 (m, 2H), 8.35 (d, 1H). LCMS m/z 493.00 (M+H), Rt=1.618 min.HPLC (Sunfire C18) Rt=7.108 min, 100% purity and (XBridge Phenyl C18)Rt=6.383 min., 99.3% purity.

5-(2-(2-Amino-2-oxoethoxy)-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 25 mL flask was added4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoic acid (48.8 mg, 0.099 mmol),DMF (2 mL), N-ethyl-N-diisopropylpropan-2-amine (0.069 mL, 0.396 mmol),1-(pyridin-2-yl)cyclopropanamine (19.94 mg, 0.149 mmol) and finally HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V), 151 mg, 0.396 mmol). The flask wassealed with a septa, placed under N₂ and stirred at room temperatureovernight. The crude product was purified using a Shimadzu preparativeHPLC employing acetonitrile/water/trifluoroacetic acid where solvent Awas 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent Bwas 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a WatersSunfire 5 μm C18 19×150 mm column at a gradient of 20-100% B and a flowrate of 25 mL/min. over 22 minutes with a 8 minute hold. The solvent wasremoved giving 53.0 mgs (87% yield) of5-(2-(2-amino-2-oxoethoxy)-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a yellow powder. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersXBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,DMF-d7) δ ppm 1.46-1.53 (m, 2H), 1.69-1.76 (m, 2H), 2.96 (d, J=4.77 Hz,3H), 4.16 (s, 3H), 4.82 (s, 2H), 7.04 (s, 1H), 7.34 (br. s., 1H),7.36-7.48 (m, 3H), 7.52 (br. s., 1H), 7.66-7.78 (m, 3H), 7.92-8.01 (m,2H), 8.03 (d, J=2.76 Hz, 1H), 8.08-8.14 (m, 2H), 8.36 (d, J=4.77 Hz,1H), 8.57-8.62 (m, 1H), 8.94 (s, 1H). LCMS m/z 609.5 (M+H), Rt=2.030min. HPLC (Sunfire C18) Rt=5.800 min, 99.4% purity and (XBridge PhenylC18) Rt=9.546 min., 99.7% purity.

2-(4-Fluorophenyl)-5-(4-hydroxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a 250 mL round-bottomed flask was added2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(1.0008 g, 1.821 mmol), and DCM (18 mL). The solution was placed underan atmosphere of nitrogen and cooled to 0° C. To the tan mixture wasadded dropwise 1M trichloroborane (9.10 mL, 9.10 mmol). The mixture wasallowed to slowly warm to room temperature overnight. The reactionmixture was cooled to 0° C. and 100 mL of cold methanol was added andthe mixture stirred for 30 minutes then evaporated to near dryness. Theaddition of methanol followed by evaporation was repeated to give a tansolid (82% yield). The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=95% HPLC grade acetonitrile/10 mM Ammonium acetate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM Ammonium acetate/5% HPLCgrade acetonitrile), in 4 minutes with a 1 minute hold at a rate of 0.8mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 1.26-1.37 (m, 2H), 1.57-1.66(m, 2H), 2.28 (s, 3H), 3.02 (d, J=4.02 Hz, 3H), 6.77 (s, 1H), 7.18 (t,J=8.78 Hz, 3 H), 7.32 (d, J=8.28 Hz, 1H), 7.51 (d, J=8.53 Hz, 1H),7.69-7.79 (m, 1H), 7.83-7.97 (m, 3H), 8.08 (s, 1H), 8.22-8.39 (m, 4H),8.66 (br. s., 1H). LCMS m/z 536.5 (M+H), 534.4 (M−H), Rt=3.446 min., 90%purity.

2-(4-Fluorophenyl)-5-(4-isopropoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide,TFA

To a microwave vial was added2-(4-fluorophenyl)-5-(4-hydroxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(16.6 mg, 0.031 mmol), dioxane (2 mL), triphenylphosphine (32.5 mg,0.124 mmol), (E)-di-tert-butyl diazene-1,2-dicarboxylate (21.41 mg,0.093 mmol) and propan-2-ol (5.92 μL, 0.077 mmol). The vial was sealedand subjected to microwave heating (140° C.) for 20 minutes. The crudeproduct was purified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25mL/min. over 20 minutes with a 5 minute hold. The solvent was removedgiving 6 mgs (25% yield) of2-(4-fluorophenyl)-5-(4-isopropoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideas a colorless powder. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold ata rate of 0.8 mL/minute. HPLC purity was determined using a Shimadzuanalytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acidwith a gradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 1.24-1.31 (m, 2H), 1.46 (d,J=6.02 Hz, 6H), 1.64-1.69 (m, 2H), 2.29 (s, 3H), 2.89 (d, J=4.52 Hz,3H), 4.83-4.95 (m, 1H), 6.98-7.04 (m, 1H), 7.07 (s, 1H), 7.16-7.24 (m,2H), 7.26 (dd, J=8.28, 1.76 Hz, 1H), 7.47 (d, J=8.03 Hz, 2H), 7.52-7.59(m, 2H), 7.62 (d, J=1.26 Hz, 1H), 7.95 (s, 1H), 8.11-8.19 (m, 2H),8.36-8.43 (m, 1H), 8.61 (s, 1H). LCMS m/z 578.4 (M+H), Rt=2.746 min.HPLC (Sunfire C18) Rt=7.695 min, 98.38% purity and (XBridge Phenyl C18)Rt=12.003 min., 95.9% purity.

Methyl2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate

To a 150 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (0.5 g, 1.198 mmol), dioxane (7.18 mL), water(1.437 mL), tetrakis (triphenylphosphine)palladium(0) (0.028 g, 0.024mmol), 4-chloro-3-(methoxycarbonyl)phenyl boronic acid (0.385 g, 1.797mmol), and cesium carbonate (0.586 g, 1.797 mmol). The tube was sealedand heated in an oil bath overnight at 85° C. The reaction mixture wascooled; the crude product was diluted with 100 mL of ethyl acetate,washed sequentially with 50 mL of water then brine. The product solutionwas dried over magnesium sulfate and filtered. Solvent was evaporated togive a crude yellow solid. The solid was triturated with diethyl ether(30 mL×2) and hexane (30 mL×1) then dried under vacuum to give 394 mgsof a ivory colored solid (53% yield). The LC/MS data was obtained on aShimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using thefollowing set of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column,with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1minute hold at a rate of 0.8 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm2.92 (d, J=4.77 Hz, 3H), 3.91 (s, 3H), 7.18-7.27 (m, 2H), 7.52-7.55 (m,1H), 7.57 (d, J=8.53 Hz, 1H), 7.63 (d, J=1.25 Hz, 2H), 7.82 (dd, J=8.41,2.38 Hz, 1H), 7.96-8.00 (m, 1H), 8.09-8.17 (m, 3H). LCMS m/z 438.3(M+H), Rt=3.518 min., 90% purity.

Methyl2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate

To a microwave vial was added dioxane (6 mL), water (0.600 mL),dicyclohexyl(2′,6′-dimethoxy biphenyl-2-yl)phosphine (S-Phos, 16.42 mg,0.040 mmol), methyl 2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (87.6 mg, 0.2 mmol), tribasicpotassium phosphate (0.170 g, 0.800 mmol), palladium(II) acetate (8.98mg, 0.040 mmol), and 2-chlorophenylboronic acid (0.094 g, 0.600 mmol).The vial was capped, degassed, flushed with N₂ and heated in themicrowave for 10 minutes at 130° C. The solvent was removed and thecrude reaction mixture was taken up in 4 mL of acetonitrile and purifiedusing a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25mL/min. over 20 minutes with a 10 minute hold. The solvent was removedto give 43.8 mgs (80% yield) of methyl2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylateas a yellow solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 2.92-2.97 (m, 3H),3.60-3.62 (m, 3H), 7.19-7.26 (m, 2H), 7.27-7.34 (m, 3H), 7.37 (d, J=8.03Hz, 1H), 7.41-7.45 (m, 1H), 7.46-7.52 (m, 1H), 7.62-7.67 (m, 1H),7.68-7.73 (m, 1H), 7.92 (dd, J=7.91, 2.13 Hz, 1H), 8.05 (d, J=1.25 Hz,1H), 8.12-8.19 (m, 2H), 8.29 (d, J=2.01 Hz, 1H). LCMS m/z 514.2 (M+H),Rt=3.908 min., 93% purity.

2′-Chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylicacid

To a 25 mL round-bottomed flask was added methyl2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate(43.8 mg, 0.079 mmol), methanol (1 mL), THF (1 mL) and 8 equivalents ofa 1M solution of sodium hydroxide (0.63 mL, 0.63 mmol). The mixture wasstirred at room temperature for 48 hours. The crude product was dilutedwith 20 mL of ethyl acetate, made acidic with 0.5M HCl, extracted,washed with brine, dried over sodium sulfate, filtered and evaporated todryness giving 47.2 mgs (96% yield) of2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylicacid as yellow solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold ata rate of 0.8 mL/minute. LCMS m/z 500.2 (M+H), Rt=3.426 min., 90%purity.

5-(2′-Chloro-2-(1-(pyridin-2-yl)cyclopropylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 25 mL flask was added2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylicacid (39.6 mg, 0.079 mmol), DMF (2 mL),N-ethyl-N,N-isopropylpropan-2-amine (0.055 mL, 0.317 mmol),1-(pyridin-2-yl)cyclopropanamine (15.94 mg, 0.119 mmol), and finallyHATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate (V), (120 mg, 0.317 mmol). The flask was sealed andthe mixture stirred over night at room temperature. The crude productwas purified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25mL/min. over 20 minutes with a 10 minute hold. Solvent was removedgiving 40.7 mgs (70% yield) of5-(2′-chloro-2-(1-(pyridin-2-yl)cyclopropylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a white solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersXBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 0.90-1.10 (m, 2H), 1.42-1.53 (m, 2H), 2.94 (d, J=4.52 Hz,3H), 7.11 (dd, J=6.90, 5.40 Hz, 1H), 7.18-7.27 (m, 2 H), 7.30-7.43 (m,5H), 7.44-7.49 (m, 1H), 7.52-7.58 (m, 1H), 7.59-7.67 (m, 2H), 7.73 (dd,J=8.53, 1.76 Hz, 1H), 7.81 (dd, J=7.78, 2.01 Hz, 1H), 7.95-8.01 (m, 2H), 8.06 (d, J=1.51 Hz, 1H), 8.09-8.17 (m, 2H), 8.41 (d, J=4.02 Hz, 1H).LCMS m/z 617.3 (M+H), Rt=2.765 min. HPLC (Sunfire C18) Rt=7.823 min,100% purity and (XBridge Phenyl C18) Rt=11.871 min., 99.8% purity.

Methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoate

To a 100 mL round-bottomed flask was added methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate(350.5 mg, 0.783 mmol) in DCM (8 mL). To this solution was then added,under nitrogen, a 1M solution of boron trichloride (3.92 mL, 3.92 mmol)and the mixture was stirred overnight at room temperature. The reactionmixture was cooled in an ice bath and 10 mL of methanol was slowlyadded. The solvent was removed under vacuum. The flask was again cooled,25 mL of ice cold methanol was added and the resulting solid wasfiltered to give 264.5 mgs (78% yield) of methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoateas an ivory colored solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold ata rate of 0.8 mL/minute. ¹H NMR (400 MHz, DMF-d7) δ ppm 2.30 (s, 3H),2.95 (d, J=4.77 Hz, 3H), 3.98 (s, 3H), 7.02 (s, 1H), 7.38-7.48 (m, 3H),7.68-7.73 (m, 2H), 7.76 (d, J=8.53 Hz, 1H), 8.08-8.15 (m, 2H), 8.33 (br.s., 1H). LCMS Rt=3.636, m/z 434.3 (M+H), 100% purity.

Methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methyl-2-(trifluoromethylsulfonyloxy)benzoate

To a 25 mL round-bottomed flask was added methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-hydroxy-4-methylbenzoate(260 mg, 0.600 mmol), DCM (6 mL), triethylamine (0.166 mL, 1.200 mmol)and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(321 mg, 0.900 mmol). The solution was stirred overnight at roomtemperature. To the reaction mixture was then added DMF (6 mL) alongwith triethylamine (0.166 mL, 1.200 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(321 mg, 0.900 mmol). The mixture was heated to 65° C. for forty eighthours. The crude product mixture was returned to room temperature,diluted with 100 mL of DCM, washed sequentially with 50 mL of cold 0.1MHCl, water and brine. The solvent was evaporated and the resulting crudeproduct was triturated with 10 mL of diethyl ether (×2) to give 180.7mgs (44.7% yield) of an ivory colored solid. The LC/MS data was obtainedon a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm usingthe following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mmcolumn, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1minute hold at a rate of 0.8 mL/minute. ¹H NMR (500 MHz, DMSO-d6) δ ppm2.37 (s, 3H), 2.82 (d, J=4.58 Hz, 3H), 3.88 (s, 3H), 7.36-7.47 (m, 3H),7.56-7.65 (m, 2H), 7.78 (d, J=8.54 Hz, 1H), 7.91 (s, 1H), 7.95-8.05 (m,2H), 8.47 (d, 1H). LCMS m/z 566.3 (M+H), Rt=3.913 min., 90% purity.

Methyl2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylate

To a small sealed tube was added methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methyl-2-(trifluoromethylsulfonyloxy)benzoate(67.3 mg, 0.1 mmol), dioxane (3 mL), water (0.600 mL),2-chlorophenylboronic acid (18.76 mg, 0.120 mmol), cesium carbonate(32.6 mg, 0.100 mmol) and tetrakis(triphenylphosphine)palladium(0)(2.311 mg, 2.000 mmol). The tube was sealed and heated overnight at 80°C. The reaction was cooled to room temperature, filtered through a plugof celite and concentrated to near dryness under a stream of nitrogen.The crude reaction mixture was taken up in 6 mL of acetonitrile andpurified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire3.5 μm C18 19×150 mm column at a gradient of 30-100% B and a flow rateof 25 mL/min. over 20 minutes with a 10 minute hold. The solvent wasremoved giving 48 mgs (89% yield) of methyl2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylateas a white solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. ¹H NMR (500 MHz, THF-d8) δ ppm 2.35 (s, 3H), 2.91 (d,J=4.58 Hz, 3 H), 3.57 (s, 3H), 7.21-7.26 (m, 3H), 7.27-7.30 (m, 1H),7.30-7.34 (m, 2H), 7.38 (dd, J=8.39, 1.68 Hz, 1H), 7.41-7.44 (m, 1H),7.50 (d, J=4.27 Hz, 1H), 7.63 (d, J=8.24 Hz, 1H), 7.75 (d, J=1.53 Hz,1H), 7.92 (s, 1H), 8.13-8.19 (m, 2H). LCMS m/z 528.4 (M+H), Rt=4.036min., 98.3% purity.

2′-Chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylic acid

To a 25 mL round-bottomed flask was added methyl2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylate(48 mg, 0.091 mmol), THF (2.2 mL), methanol (2.2 mL), and aqueous 1Msodium hydroxide (0.728 mL, 0.728 mmol). The flask was sealed andstirred at room temperature for 48 hours. Volatiles were removed and thecrude product was diluted with 30 mL of ethyl acetate, washedsequentially with 10 mL of 1M HCl, brine, dried over sodium sulfate,filtered and evaporated to dryness. The resulting product was trituratedwith 10 mL of diethyl ether giving 47.2 mgs (96% yield) of2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylicacid as a yellow solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold ata rate of 0.8 mL/minute. ¹H NMR (400 MHz, DMF-d7) δ ppm 2.42 (s, 3H),2.97 (d, J=4.52 Hz, 3H), 7.30 (s, 1H), 7.39-7.48 (m, 5H), 7.50-7.57 (m,2H), 7.78-7.85 (m, 2H), 7.99 (s, 1H), 8.10-8.17 (m, 2H), 8.35-8.43 (m,1H). LCMS m/z 514.3 (M+H), Rt=3.950 min., 95.4% purity.

5-(2′-Chloro-5-methyl-2-(1-(pyridin-2-yl)cyclopropylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,TFA

To a 25 mL flask was added2′-chloro-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methylbiphenyl-2-carboxylicacid (47.2 mg, 0.087 mmol), DMF (2 mL),N-ethyl-N,N-diisopropylpropan-2-amine (0.061 mL, 0.349 mmol),1-(pyridin-2-yl)cyclopropanamine (17.56 mg, 0.131 mmol) and finally HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V), 133 mg, 0.349 mmol). The flask was sealed with asepta, placed under N₂ and stirred at room temperature for 5 hours. Thecrude product was purified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 30-100% B and a flow rate of 25mL/min. over 20 minutes with a 10 minute hold. The solvent wasevaporated to give 66.1 mgs (92% yield) of5-(2′-chloro-5-methyl-2-(1-(pyridin-2-yl)cyclopropylcarbamoyl)biphenyl-4-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a white solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/trifluoroacetic acid with a gradient of10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersXBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 0.85-0.96 (m, 1H), 0.99-1.09 (m, 1H), 1.38-1.53 (m, 2H),2.33 (s, 3H), 2.90 (d, J=4.52 Hz, 3H), 7.07-7.14 (m, 1H), 7.20-7.28 (m,3H), 7.30-7.36 (m, 3H), 7.37-7.42 (m, 2H), 7.44-7.49 (m, 1H), 7.56 (d,J=4.52 Hz, 1H), 7.58-7.65 (m, 3H), 7.77 (d, J=1.51 Hz, 1H), 7.89 (s,1H), 8.10-8.18 (m, 2H), 8.37-8.42 (m, 1H). LCMS m/z 631.39 (M+H),Rt=2.925 min. HPLC (Sunfire C18) Rt=8.118 min, 99.9% purity and (XBridgePhenyl C18) Rt=11.519 min., 100% purity.

2-Chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

Alternative Procedure: To a 150 mL sealed tube was added2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (1.0 g, 2.4 mmol), dioxane (14.4 mL), water(2.9 mL), tetrakis(triphenyl phosphine)palladium(0) (0.055 g, 0.048mmol), 5-borono-2-chlorobenzoic acid (0.720 g, 3.59 mmol), and cesiumcarbonate (1.171 g, 3.59 mmol). The tube was sealed and heated in an oilbath overnight at 85° C. The reaction mixture was cooled, diluted with150 mL of ethyl acetate, washed sequentially with 20 mL of 0.5M HCl thenbrine. The product solution was filtered through a plug of celite thenevaporated to dryness. The resulting solid was taken up in 10 mL of 1:1DMF and acetonitrile and purified using a Shimadzu preparative HPLCemploying acetonitrile/water/trifluoroacetic acid where solvent A was10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was10% water/90% acetonitrile/0.1% trifluoroacetic acid with a WatersSunfire 3.5 μm C18 4.6×150 mm column at a gradient of 50-100% B and aflow rate of 40 mL/min. over 20 minutes with a 5 minute hold. Solventwas evaporated giving 319.5 mgs (32% yield) of2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid as a white powder. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 10 μm C18, 3.0×50 mm column, with agradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade methanol), in 4 minutes with a 1 minute hold at arate of 5 mL/minute. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.83-2.91 (m, 3H),7.35-7.45 (m, 2H), 7.65 (d, J=8.53 Hz, 1H), 7.69-7.75 (m, 1H), 7.76-7.82(m, 1H), 7.85-7.93 (m, 2H), 7.98-8.05 (m, 2H), 8.08 (d, J=2.26 Hz, 1H),8.43-8.53 (m, 1H), 13.50 (br. s., 1H). LCMS m/z 424.0 (M+H), Rt=3.105min., 100% purity.

5-(4-Chloro-3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 250 mL round-bottomed flask was added2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (0.299 g, 0.705 mmol), 1-(pyridin-2-yl)cyclopropanamine (0.142 g,1.058 mmol), DMF (8.50 mL), N-ethyl-N,N-diisopropylpropan-2-amine (0.493mL, 2.82 mmol), and HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V), 1.073 g, 2.82 mmol). The flask was sealed,placed under N₂ and stirred overnight at room temperature. The reactionmixture was diluted with 50 mL of ethyl acetate, washed with 5 mL of 1MHCl, extracted, dried over magnesium sulfate, filtered and evaporated toa red oil. The crude reaction mixture was then evacuated to neardryness, taken up in 8 mL of 1:1 methanol and DMF and purified using aShimadzu preparative HPLC employing methanol/water/trifluoroacetic acidwhere solvent A was 10% methanol/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% methanol/0.1% trifluoroacetic acid with aPhenomenex-Luna 10 μm C18 30×100 mm column at a gradient of 50-100% Band a flow rate of 40 mL/min. over 8 minutes with a 7 minute hold.Solvent was evaporated giving 261.3 mgs (66.4% yield) of5-(4-chloro-3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide asa light yellow solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Waters Sunfire 5 μm C18, 4.6×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 3 minutes with a 1 minute hold ata rate of 4 mL/minute. HPLC purity was determined using a Shimadzuanalytical LC at 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm4.6×150 mm column employing water/acetonitrile/0.1% trifluoroacetic acidwith a gradient of 20-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Phenomenex Gemini C18 3.0 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of20-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.40 (m, 2H), 1.56-1.64(m, 2H), 2.83-2.91 (m, 3H), 7.27 (dd, J=6.78, 5.27 Hz, 1H), 7.35-7.45(m, 2H), 7.63 (d, J=8.28 Hz, 1H), 7.69-7.96 (m, 7H), 7.97-8.06 (m, 2H),8.50 (d, J=4.52 Hz, 2H), 9.34 (s, 1H). LCMS m/z 540.39 (M+H), Rt=1.643min., 94.2% purity. HPLC (Sunfire C18) Rt=6.388 min, 94% purity and(Gemini C18) Rt=11.238 min., 99.6% purity.

Methyl2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate

To a microwave vial was added dioxane (9 mL), water (0.900 mL),2-carbamoylphenylboronic acid (148 mg, 0.900 mmol), methyl2-chloro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate(131 mg, 0.3 mmol), tribasic potassium phosphate (255 mg, 1.200 mmol),dicyclohexyl (2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos, 24.63 mg,0.060 mmol), and palladium(II) acetate (13.47 mg, 0.060 mmol). The vialwas capped, degassed, flushed with N₂ and heated in the microwave for 13minutes at 130° C. The reaction mixture was filtered and solvent removedunder a stream of nitrogen. The crude product was then taken up in 4 mLof acetonitrile and purified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25mL/min. over 20 minutes with a 10 minute hold. The solvent was removedgiving 58.3 mgs (36% yield) of methyl2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylateas a yellow solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. ¹H NMR (400 MHz, THF-d8) δ ppm 2.93 (d, J=4.52 Hz, 3H),3.62 (s, 3H), 6.35 (br. s., 2H), 7.09-7.15 (m, 1H), 7.22 (t, J=8.91 Hz,2H), 7.31-7.43 (m, 3H), 7.52 (d, J=4.27 Hz, 1H), 7.58-7.71 (m, 3H), 7.81(dd, J=8.03, 2.01 Hz, 1H), 8.01 (d, J=1.25 Hz, 1H), 8.09-8.20 (m, 3H).LCMS m/z 523.3 (M+H), Rt=3.051 min., 96% purity.

2′-Carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylicacid

To a 25 mL round-bottomed flask was added methyl2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylate(58.3 mg, 0.107 mmol), methanol (1 mL), THF (1 mL) and 8 equivalents ofa 1M solution of sodium hydroxide (0.856 mL, 0.856 mmol). The mixturewas diluted with 20 mL of ethyl acetate, made acidic with 0.5M HCl andthe crude product was extracted, washed with brine, and dried oversodium sulfate. The product solution was filtered and evaporated todryness giving 52 mgs (98% yield) of2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylicacid as a yellow solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold ata rate of 0.8 mL/minute. LCMS m/z 509.3 (M+H), Rt=2.695 min., 90%purity.

4-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-N2-(1-(pyridin-2-yl)cyclopropyl)biphenyl-2,2′-dicarboxamide,TFA

To a 25 mL round-bottomed flask was added2′-carbamoyl-4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)biphenyl-2-carboxylicacid (52 mg, 0.104 mmol), DMF (2 mL),N-ethyl-N,N-isopropylpropan-2-amine (0.075 mL, 0.429 mmol),1-(pyridin-2-yl)cyclopropanamine (21.57 mg, 0.161 mmol) and finally HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluoro phosphate (V), 163 mg, 0.429 mmol). The flask was sealed andthe mixture stirred at room temperature over night. The crude productwas purified using a Shimadzu preparative HPLC employingacetonitrile/water/trifluoroacetic acid where solvent A was 10%acetonitrile/90% water/0.1% trifluoroacetic acid and solvent B was 10%water/90% acetonitrile/0.1% trifluoroacetic acid with a Waters Sunfire 5μm C18 19×150 mm column at a gradient of 20-100% B and a flow rate of 25mL/min. over 20 minutes with a 10 minute hold. The solvent wasevaporated giving 2 rotomers as shown above. The LC/MS data was obtainedon a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm usingthe following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mmcolumn, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1minute hold at a rate of 0.8 mL/minute. HPLC purity was determined usinga Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1%trifluoroacetic acid with a gradient of 10-100% B (B=95% HPLC gradeacetonitrile/0.1% trifluoroacetic acid/5% HPLC grade water), (A=95% HPLCgrade water/0.1% trifluoroacetic acid/5% HPLC grade acetonitrile), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. The HPLC puritywas then confirmed with an orthogonal solvent system and column using aShimadzu analytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150mm column employing water/methanol/10 mM ammonium bicarbonate with agradient of 10-100% B (B=95% HPLC grade methanol/10 mM ammoniumbicarbonate/5% HPLC grade water), (A=95% HPLC grade water/10 mM ammoniumbicarbonate/5% HPLC grade methanol), in 10 minutes with a 10 minute holdat a rate of 1 mL/minute. Isomer A: ¹H NMR (400 MHz, THF-d8) δ ppm0.53-0.79 (m, 2H), 1.36 (d, J=4.27 Hz, 2H), 2.95 (d, J=4.52 Hz, 3H),6.79 (br. s., 1H), 6.88-7.00 (m, 2H), 7.16-7.26 (m, 4H), 7.39 (td,J=7.72, 1.88 Hz, 1H), 7.46-7.53 (m, 3H), 7.57-7.61 (m, 1H), 7.61-7.65(m, 2H), 7.69 (ddd, J=10.23, 8.22, 1.88 Hz, 2H), 7.91 (d, J=2.01 Hz,1H), 8.04 (d, J=1.51 Hz, 1H), 8.13-8.19 (m, 2H), 8.25-8.31 (m, 1H), 9.01(s, 1H). LCMS m/z 625.4 (M+H), Rt=2.310 min. HPLC (Sunfire C18) Rt=6.796min, 100% purity and (XBridge Phenyl C18) Rt=10.793 min., 100% purity.Isomer B: ¹H NMR (400 MHz, THF-d8) δ ppm 0.64-0.92 (m, 2H), 1.39 (d,J=4.02 Hz, 2H), 2.93 (d, J=4.77 Hz, 3H), 6.76 (br. s., 1H), 6.88 (dd,J=6.90, 5.14 Hz, 1H), 6.96 (d, J=8.03 Hz, 1H), 7.11-7.18 (m, 1H),7.20-7.30 (m, 3H), 7.31-7.43 (m, 3H), 7.50 (br. s., 1H), 7.59 (dd,J=7.15, 1.88 Hz, 1H), 7.62-7.67 (m, 1H), 7.68-7.76 (m, 2H), 7.82 (dd,J=7.78, 2.01 Hz, 1H), 7.92 (d, J=1.76 Hz, 1H), 8.07 (d, J=1.76 Hz, 1H),8.09-8.17 (m, 2H), 8.26 (d, J=4.27 Hz, 1H), 8.98 (s, 1H). LCMS m/z 625.4(M+H), Rt=2.275 min. HPLC (Sunfire C18) Rt=6.688 min, 100% purity and(XBridge Phenyl C18) Rt=10.821 min., 100% purity.

Ethyl 4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate

To a mixture of ethyl2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (500 mg, 1.665mmol) in acetonitrile (10 mL) at r.t. under N₂ was added1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanetetrafluoroborate (708 mg, 1.998 mmol). The mixture was stirred at r.t.(the mixture turned bright yellow in color) for 20 hours. The mixturewas evaporated. The residue was added with 10 ml H₂O. The aqueousdecanted, and the residue further washed with 2×5 ml H₂O. The mixturewas dissolved in MeOH (about 10 ml), and the insoluble filtered. Thefiltrate was purified by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA,Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=60, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.44-7.24 min. (UVdetection at 220 nm). The desired fractions were combined and evaporatedto give a yellow solid. The yellow solid was further purified by BiotageHorizon flash chromatography (0 to 70% EtOAc/Hexane, 3×80 g silica gelcolumn) to give a light yellow solid (108.9 mg). ¹H NMR (500 MHz, CD₃OD)δ 7.95 (m, 2H), 7.26 (t overlapping with dd, 2H), 7.25 (dd, 1H), 7.03(t, J=8.39, 1H), 4.39 (q, J=7.17, 2H), 1.36 (t, J=7.17, 3H). ¹⁹F NMR(470.45 MHz, CD₃OD) δ −112.36, −142.29. The position of the F atom at C4was confirmed by ¹H-¹H through bond correlation between H6 and H7,¹H-¹³C HMBC and F—C4 coupling in ¹³C NMR (125.75 MHz, CD₃OD) (δ 144.8ppm, d, J=247, C4). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z(M+H)⁺=319.14, HPLC Rt=1.718 min. The minor fractions collected at about7.69-8.20 min. was confirmed by ¹H-¹H through bond correlation, ¹H-¹³CHMBC and F—C6 coupling in ¹³C NMR (125.75 MHz, CD₃OD) (δ 152.5 ppm, d,J=242 Hz, C6) to be the isomer of the F-atom at C6 (C4: C6 about 3:1based on preparative HPLC % area of the UV trace); ¹H NMR (500 MHz,CD₃OD) δ 8.04 (dd, J=8.55, 5.49, 2H), 7.59 (d, J=8.85, 1H), 7.38 (d,J=10.07, 1H), 7.25 (t, J=8.70, 2H), 4.40 (q, J=7.17, 2H), 1.41 (t,J=7.17, 3H). ¹⁹F NMR (470.45 MHz, CD₃OD) δ −112.29, −138.52. LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=319.14, HPLCR_(t)=1.798 min.

4-Fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid

To a mixture of ethyl4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (108.9 mg,0.342 mmol) in a mixture of MeOH (2 mL)/THF (2 mL) at r.t. under N₂ wasadded sodium hydroxide (1.0 mL, 1.0 mmol) (1 M aq.). The mixture wasstirred at 100° C. for 1.5 hours. The mixture was cooled to r.t., addedwith 1.5 ml 1N HCl, and then added 10 ml H₂O. The white precipitateswere filtered and washed with 3×2 ml H₂O and dried (73 mg). ¹H NMR (500MHz, CD₃OD) δ 7.98 (m, 2H), 7.25 (t overlapping with dd, 2H), 7.24 (dd,1H), 7.02 (t, J=8.39, 1H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=291.01, HPLC Rt=1.478 min.

4-Fluoro-2-(4-fluorophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide

To a mixture of4-fluoro-2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid (73mg, 0.252 mmol), methylamine, HCl (25.5 mg, 0.377 mmol), HOBT hydrate(65.5 mg, 0.428 mmol) and EDC hydrochloride (87 mg, 0.453 mmol) at r.t.under N₂ was added N,N-diisopropylethylamine (0.220 mL, 1.258 mmol). Themixture was stirred at r.t. for 16 hours. After concentration, themixture was added with 5 ml 1N HCl, and then 14 ml H₂O. The white solidwas filtered and washed with 3×5 ml H₂O and dried (64 mg). ¹H NMR (500MHz, CD₃OD) δ 7.89 (dd, J=8.09, 5.34, 2H), 7.25 (t overlapping with dd,2H), 7.23 (dd, 1H), 6.99 (t, J=8.55, 1H), 2.96 (s, 3H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=304.06, HPLC Rt=1.262min.

4-Fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate

To a white suspension of4-fluoro-2-(4-fluorophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide(64 mg, 0.211 mmol) in CH₂Cl₂ (2 mL) at r.t. under N₂ was addedtriethylamine (0.059 mL, 0.422 mmol). The mixture was cooled to 0° C.,and then added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(113 mg, 0.317 mmol). The mixture was then stirred at r.t. (the whitesuspension turned into a light yellow solution after stirring for about10 min) for 2 hours 35 min. The mixture was left standing at r.t.overnight, and then evaporated. The residue was cooled in an ice-waterbath, added with 2 ml H₂O. The solids were filtered and washed with 3×2ml H₂O, and dried (94 mg). ¹H NMR (500 MHz, CD₃OD) δ 7.95 (m, 2H), 7.59(dd, J=9.00, 1.00, 1H), 7.50 (dd, J=9.00, 7.50, 1H), 7.30 (t, J=8.55,2H), 2.99 (s, 3H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z(M+H)⁺=436.04, HPLC Rt=1.678 min.

Methyl5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate

A mixture of the above prepared4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate(assumed 0.211 mmol), methyl2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(0.078 g, 0.253 mmol), (Ph₃P)₄Pd (0.024 g, 0.021 mmol) and cesiumcarbonate (0.103 g, 0.317 mmol) in a mixture of H₂O (0.2 mL)/1,4-dioxane(1 mL) was stirred at 95° C. for 2 hours 30 min. The mixture was leftstanding at r.t. overnight. The mixture was diluted with 3.5 ml1,4-dioxane, filtered through a Whatman PVDF 0.45 um disk (with 3×1 mlwashing). The filtrate was concentrated. The mixture was added with 3.5ml 1N HCl, and then 6 ml H₂O (yellow solid deposited on the wall of theflask). The aqueous was decanted, and the residue washed with 3×2 ml H₂Oand dried. LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=466.27, HPLCR_(t)=1.708 min.

5-(4-Fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid

To the above prepared methyl5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate(assumed 0.211 mmol) in a mixture MeOH (2 mL)/THF (2 mL) at r.t. underN₂ was added sodium hydroxide (0.84 mL, 0.84 mmol). The mixture wasstirred at r.t. for 24 hours. The mixture was added with 2 ml 1N HCl,and concentrated until off white solids formed. The mixture was addedwith 5 ml H₂O, the solids filtered and washed with 3×2 ml H₂O and dried(75.1 mg). ¹H NMR (500 MHz, CD₃OD) δ 7.95 (m, 2H), 7.73 (s, 1H), 7.51(d, J=8.24, 1H), 7.30-7.25 (t overlapping with m, 3H), 7.13 (s, 1H),3.99 (s, 3H), 2.96 (s, 3H), 2.28 (s, 3H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=452.23, HPLC R_(t)=1.582.

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (30 mg, 0.066 mmol), 1-(pyrimidin-2-yl)cyclopropanamine, TFA (33.1mg, about 75% pure, assumed 0.133 mmol,) and2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumtetrafluoroborate (64.0 mg, 0.199 mmol) in DMF (1 mL) at r.t. under N₂was added N,N-diisopropylethyl amine (0.058 mL, 0.332 mmol). The mixturewas stirred at r.t. for 20 hours. The mixture was diluted with MeOH andpurified by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90%MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire19×100 mm S5, UV detection at 220 nm, Fraction Collection: 7.25-7.73min. The residue after evaporation of the combined fractions was furtherpurified by preparative TLC (two of 500 um×20×20 cm plates, 5%MeOH/CH₂Cl₂) to give4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideas a white solid. Analytical TLC Rf=0.32 (5% MeOH/CH₂Cl₂). ¹H NMR (500MHz, CD₃OD) δ 8.65 (d, J=4.88, 2H), 7.95 (m, 2H), 7.89 (s, 1H), 7.50 (d,J=8.55, 1H), 7.28 (t, J=8.70, 2H), 7.28-7.25 (m overlapping with t, 1H),7.23 (t, J=4.88, 1H), 7.17 (s, 1H), 4.09 (s, 3H), 2.95 (s, 3H), 2.30 (s,3H), 1.79 (m, 2H), 1.51 (m, 2H). ¹⁹F NMR (470.45 MHz, CD₃OD) δ −112.81,−123.16. LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=569.38, HPLCRt=1.660 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=6.29 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=5.18 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=9.39 min.

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)propylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)propylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamidewas formed as a minor side product during the synthesis of4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideas described above, and was isolated during purification by preparativereverse phase HPLC (Fraction Collection: 7.82-8.48 min) ¹H NMR (500 MHz,DMSO-d₆) δ 9.08 (d, J=7.32, 1H), 8.87 (d, J=4.88, 2H), 8.70 (q, J=4.58,1H), 7.94 (m, 2H), 7.78 (s, 1H), 7.62 (d, J=8.24, 1H), 7.46 (t, J=4.88,1H), 7.42 (t, J=9.00, 2H), 7.30 (dd, J=8.39, 7.17, 1H), 7.24 (s, 1H),5.16 (m, 1H), 4.08 (s, 3H), 2.80 (d, J=4.58, 3H), 2.24 (s, 3H), 1.97 (m,2H), 0.82 (t, J=7.32, 3H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=571.35, HPLC R_(t)=1.743 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=7.33 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.69 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=10.23 min.

5-(5-(Ethylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

5-(5-(Ethylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamidewas formed as a minor side product during the synthesis of4-fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideas described above, and was isolated during purification by preparativeTLC (the band right above the major product band). ¹H NMR (500 MHz,CD₃OD) δ 7.95 (m, 2H), 7.81 (s, 1H), 7.51 (d, J=8.55, 1H), 7.30-7.25 (toverlapping with dd, 3H), (7.13 (s, 1H), 4.04 (s, 3H), 3.46 (q, J=7.17,2H), 2.95 (s, 3H), 2.28 (s, 3H), 1.25 (t, J=7.17, 3H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=479.30, HPLCR_(t)=1.670 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=6.94 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=5.31 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=9.20 min.

Methyl2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of methyl 5-iodo-2,4-dimethylbenzoate (1 g, 3.45 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.050 g,4.14 mmol), potassium acetate (1.015 g, 10.34 mmol) andPdCl₂(dppf)(Cl₂CH₂)([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane) (0.284 g, 0.345 mmol) in DMF (25 mL) under N₂ wasstirred at 100° C. for 20 hours. The mixture was cooled to r.t., addedwith 30 ml H₂O. The dark solid was filtered and washed with 3×5 ml H₂Oand dried. The solid was purified by Biotage Horizon flashchromatography (0 to 70% EtOAc/Hexane) to give the product as a whitesolid (442.7 mg). ¹H NMR (500 MHz, CD₃OD) δ 8.26 (s, 1H), 7.11 (s, 1H),3.88 (s, 3H), 2.56 (s, 3H), 2.53 (s, 3H), 1.37 (s, 12H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=291.14, HPLCR_(t)=1.933 min.

3-(4-Fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=422.19, HPLCR_(t)=1.653 min.

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.80-7.18 min. (UVdetection at 220 nm). The material obtained was further purified bypreparative TLC (500 um×20×20 cm plate, 5% MeOH/CH₂Cl₂). Analytical TLCRf=0.35 (5% MeOH/CH₂Cl₂). ¹H NMR (500 MHz, CD₃OD) δ 8.64 (d, J=4.88,2H), 7.96 (m, 2H), 7.90 (dd, J=7.93, 1.83, 1H), 7.84 (d, J=1.83, 1H),7.54 (d, J=8.54, 1H), 7.46 (d, J=7.93, 1H), 7.34-7.27 (m overlappingwith t, 3H), 7.22 (t, J=4.88, 1H), 2.96 (s, 3H), 2.29 (s, 3H), 1.77 (m,2H), 1.46 (m, 2H). ¹⁹F NMR (470.45 MHz, CD₃OD) δ −112.72, −123.10. LC/MSwere performed by using Shimadzu-VP instrument with UV detection at 220nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=539.32, HPLC Rt=1.585min. Analytical HPLC were performed by using Shimadzu-VP instrument withUV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=5.64 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=4.66 min. Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=8.43 min.

5-(5-(tert-Butylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 8.68-9.29 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 7.88 (dd, J=8.55, 5.19,2H), 7.72 (s, 1H), 7.43 (d, J=8.55, 1H), 7.23-7.17 (overlapping m, 3H),7.06 (s, 1H), 3.98 (s, 3H), 2.89 (s, 3H), 2.20 (s, 3H), 1.41 (s, 9H).LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=507.33, HPLCR_(t)=1.837 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=10.19 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=7.50 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=11.25 min.

Methyl5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2,4-dimethylbenzoate

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=450.11, HPLCR_(t)=1.852 min.

5-(4-Fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2,4-dimethylbenzoicacid

¹H NMR (500 MHz, CD₃OD) δ 7.95 (m, 2H), 7.80 (s, 1H), 7.51 (d, J=8.55,1H), 7.30-7.25 (s and overlapping m, 4H), 2.96 (s, 3H), 2.63 (s, 3H),2.23 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument withUV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=436.09, HPLCR_(t)=1.735 min.

5-(2,4-Dimethyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Sunfire Prep C18 19×100 5 um, Fraction Collection: 6.93-7.43 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, DMSO-d₆, peaks were generallybroad) δ 8.93 (s, 1H), 8.71 (broad s, 1H), 8.68 (m, 2H), 7.93 (m, 2H),7.65 (m, 1H), 7.44 (m, 2H), 7.33 (m, 2H), 7.27 (m, 1H), 7.25 (m, 1H),2.81 (s, 3H), 2.45 (s, 3H), 2.17 (s, 3H), 1.57 (s, 2H), 1.33 (s, 2H).¹⁹F NMR (470.45 MHz, DMSO-d₆) δ −110.88, −121.61. LC/MS were performedby using Shimadzu-VP instrument with UV detection at 220 nm and WatersMicromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, SolventB=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna,3.0×50 mm, S10; (ES+) m/z (M+H)⁺=553.22, HPLC R_(t)=1.645 min.Analytical HPLC were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.26 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=5.23 min. Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=9.00 min.

Methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2,4-dimethylbenzoate

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=432.10, HPLCR_(t)=1.928 min.

5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2,4-dimethylbenzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=418.10, HPLCR_(t)=1.810 min.

5-(2,4-Dimethyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.75-8.16 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 8.67 (d, J=4.88, 2H),7.97 (m, 2H), 7.65 (s overlapped with d, 1H), 7.64 (d, J=8.50, 1H), 7.50(s, 1H), 7.38 (dd, J=8.55, 1.83, 1H), 7.28 (t, J=8.85, 2H), 7.24 (t,J=4.88, 1H), 7.22 (s, 1H), 2.95 (s, 3H), 2.52 (s, 3H), 2.30 (s, 3H),1.76 (m, 2H), 1.46 (m, 2H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=535.23, HPLC R_(t)=1.722 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=7.24 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.62 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=9.24 min.

5-(5-(1-Cyanocyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=498.21, HPLCR_(t)=1.647 min.

2-(4-Fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA,Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=30, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 6.82-7.62 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 7.96 (dd, J=8.24, 5.80,2H), 7.88 (s, 1H), 7.63 (d, J=8.24, 1H), 7.57 (s, 1H), 7.32 (d, J=8.54,1H), 7.28 (t, J=8.70, 2H), 7.13 (s, 1H), 4.05 (s, 3H), 2.96 (s, 3H),2.36 (s, 3H), 1.67 (m, 2H), 1.50 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=531.22, HPLC R_(t)=1.457 min.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamidewas prepared from2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamideunder similar conditions as described but using PhMe as a solvent. Thecrude mixture was purified by preparative TLC (20×20 cm×500 um plates,5% MeOH/CH₂Cl₂) to give the product, which was further purified byShimadzu-VP preparative reverse phase HPLC using the separation method:Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1%TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 7.95-8.47 min. (UV detection at 220 nm). Analytical TLCRf=0.38 (5% MeOH/CH₂Cl₂). ¹H NMR (500 MHz, CD₃OD) δ 7.97 (dd, J=7.93,5.49, 2H), 7.87 (s, 1H), 7.62 (d, J=8.24, 1H), 7.58 (s, 1H), 7.33 (d,J=8.55, 1H), 7.27 (t, J=8.39, 2H), 7.11 (s, 1H), 4.05 (s, 3H), 2.96 (s,3H), 2.54 (s, 3H), 2.36 (s, 3H), 1.60 (m, 2H), 1.45 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=555.34, HPLCR_(t)=1.735 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=7.75 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=5.93 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=11.98 min.

5-(2-Chloro-5-(1-cyanocyclopropylcarbamoyl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=518.20, 520.18, HPLCR_(t)=1.692 min.

5-(2-Chloro-5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=551.21, HPLCR_(t)=1.478 min.

5-(2-Chloro-4-methoxy-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The mixture first purified by by Shimadzu-VP preparative reverse phaseHPLC using the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=60, Final % B=100,Gradient time=5 min, Stop time=6 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×50 mm S5, Fraction Collection: 3.85-4.21 min. (UVdetection at 220 nm). The residue obtained after evaporation of thedesired fractions was further purified by preparative TLC (5%MeOH/CH₂Cl₂, 20 cm×20 cm×0.5 mm plates). ¹H NMR (500 MHz, CD₃OD) δ 7.98(dd overlapping with s, J=5.19, 2H), 7.97 (s, 1H), 7.71 (d, J=1.22, 1H),7.65 (d, J=8.55, 1H), 7.45 (dd, J=8.55, 1.83, 1H), 7.36 (s, 1H), 7.28(t, J=8.85, 2H), 4.05 (s, 3H), 2.96 (s, 3H), 2.54 (s, 3H), 1.61 (m, 2H),1.46 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument withUV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=4 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=575.10, HPLCR_(t)=1.817 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=7.92 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=6.21 min.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-phenyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

The mixture was first purified by Shimadzu-VP preparative reverse phaseHPLC using the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Waters-Sunfire 19×100 mm S5, Fraction Collection: 9.11-9.39 min. (UVdetection at 220 nm) to isolate the desired product. The residue afterevaporation of the desired fractions was further purified by preparativeTLC (5% MeOH/CH₂Cl₂, 20 cm×20 cm×0.5 mm plate). Analytical TLC Rf=0.52(5% MeOH/CH₂Cl₂). ¹H NMR (500 MHz, CD₃OD) δ 8.11 (d, J=7.02, 2H), 7.99(m, 2H), 7.84 (s, 1H), 7.83 (m overlapping with s, 1H), 7.68-7.64(overlapping m, 3H), 7.60-7.57 (overlapping m, 2H), 7.45 (d, J=8.55,1H), 7.40 (d, J=8.24, 1.83, 1H), 7.28 (m, 2H), 2.96 (s, 3H), 2.36 (s,3H), 1.72 (m, 2H), 1.50 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=4 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=587.20, HPLC R_(t)=1.950 min.

3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=408.15, HPLCR_(t)=1.757 min.

5-(3-Fluoro-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product precipitated from the reaction mixture during the couplingof3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid (0.068 mmol scale) with 1-(pyridin-2-yl)cyclopropanaminedihydrochloride (TBTU, iPr₂NET, DMF, r.t.). The mixture was diluted with4 ml H₂O, the off white solid filtered and washed with 3×2 ml H₂O. Thesolid was further washed with 3×1 ml MeOH and dried. ¹H NMR (500 MHz,DMSO-d₆) δ 9.50 (s, 1H), 8.52 (d, J=4.58, 1H), 8.47 (d, J=3.97, 1H),8.17 (s, 1H), 8.03-8.00 (overlapping m, 3H), 7.83 (overlapping m, 3H),7.73 (d, 1H), 7.70 (dt overlapping with d, 1H), 7.43-7.40 (overlappingm, 3H), 7.17 (dd, J=6.87, 5.34, 1H), 2.88 (d, J=4.27, 3H), 1.59 (m, 2H),1.32 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument withUV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=524.25, HPLCR_(t)=1.512 min.

Ethyl2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=436.01, HPLCR_(t)=1.820 min.

2-Fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoicacid

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=408.01, HPLCR_(t)=1.623 min.

5-(2-Fluoro-3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

The product was obtained as a TFA salt after purification by Shimadzu-VPpreparative reverse phase HPLC using the separation method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=10, Final % B=100, Gradient time=10 min, Stop time=12 min, FlowRate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, FractionCollection: 8.11-8.43 min. (UV detection at 220 nm). ¹H NMR (500 MHz,CD₃OD) δ 8.64 (d, J=5.19, 1H), 8.42 (t, J=7.78, 1H), 7.97 (dd, J=8.24,5.49, 2H), 7.91 (d, J=8.24, 1H), 7.88 (s, 1H), 7.80 (q, J=6.61, 2H),7.76 (t, J=7.17, 1H), 7.71 (d, J=8.55, 1H), 7.60 (d, J=8.24, 1H), 7.43(t, J=7.78, 1H), 7.29 (t, J=8.55, 2H), 2.97 (s, 3H), 1.84 (m, 2H), 1.74(m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=524.08, HPLCRt=1.417 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=8.57 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=9.09 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=12.08 min.

Ethyl 3-(4-Fluorophenyl)-3-oxopropanoate

To a suspension of diethyl carbonate (7.69 g, 65.14 mmol, 1.8 eq) andNaH (hexane washed) (90.47 mmol, 2.5 eq) in dry THF (30 ml)p-fluoroacetophenone (36.19 mmol) was added dropwise at 60° C. Thereaction was maintained at gentle reflux by adjusting the temperatureand the addition rate (exothermic). After the addition was complete, thereaction was heated at reflux for 4 h, and then cooled to roomtemperature. The reaction mixture was poured carefully into ice coldacetic acid (6.0 ml) and water (20 ml). The product was extracted withether, and the combined ether layers were washed with saturated aqueousbicarbonate, brine and dried. Ether was evaporated and the crude productwas purified by silica gel (60-120) column chromatography using 2%EtOAc/hexane as eluent. Yield: 7.3 g (96%). ¹H NMR (400 MHz, CDCl₃): δ1.27 (t, 3H, J=7.12 Hz), 3.96 (s, 2H), 4.24 (q, 2H, J=7.12 Hz), 7.17 (t,2H, J=7.59 Hz), 7.98 (m, 2H). LCMS: (ES+) m/z=211 (M+H).

Ethyl 2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate

To a stirred solution of zinc chloride (8.39 g, 1.14 mmol, 1 eq) intoluene at ambient temperature, ethyl 3-(4-fluorophenyl)-3-oxopropanoate(13 g, 2.74 mmol, 1 eq) was added and stirred at 70° C. for 15 min.Benzoquinone (6.66 g, 0.72 mmol, 1 eq) was added portion wise into thereaction mixture and stirred at the same temperature for 15-20 min.Dean-stark apparatus was assembled and the reaction mixture was heatedat 140° C. for 12 h and cooled to ambient temperature. Reactioncompletion was judged by TLC. EtOAc was added to the reaction mass andfiltered through the filter paper, to remove the inorganic material.Brine was added to the reaction mixture (filtrate) and extracted, driedover sodium sulphate and concentrated to get the crude material. Furtherit was purified by column chromatography using 10% EtOAc/Hexane system.Yield: 8.0 g (43%). ¹H NMR (400 MHz, CDCl₃): δ 1.38-1.42 (t, 3H, J=7.14Hz), 4.37-4.42 (q, 2H, J=7.13 Hz), 5.2 (br s, 1H), 6.87-6.9 (q, 1H,J=3.81 Hz), 7.14-7.18 (q, 2H, J=5.82 Hz), 7.36-7.39 (d, 1H, J=8.80 Hz),7.50-7.51 (d, 1H, J=2.56 Hz), 8.00-8.03 (m, 2H). LCMS: (ES+) m/z=301(M+H).

2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid

To a mixture of 2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (1g, 3.5 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperaturewas added 5 eq. of NaOH and heated to 60° C. for 3 h. The mixture wascooled to ambient temperature and to 0° C. in an ice-water bath, it wasacidified slowly with 1.5 N HCl and then concentrated. The mixture withwhite precipitates was diluted with water and filtered to get the solid.It is further washed with water and dried in vacuum. Yield: 0.9 g(94.6%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.82-6.85 (m, 1H), 7.35-7.40 (m,3H), 7.46-7.49 (d, 1H, J=8.84 Hz), 8.02-8.05 (m, 2H), 9.4 (s, 1H), 13.05(s, 1H). LCMS: (ES−) m/z=271.1

2-(4-fluorophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide

To a mixture of 2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylic acid(1 g, 3.7 mmol, 1 eq), methylamine in THF (2 M solution) (0.689 g, 21.5mmol, 1 eq), HOBT (0.83 g, 6.2 mmol, 1.7 eq), EDC.HCl (1.24 g, 6.6 mmol,1.8 eq) in DMF at ambient temperature under nitrogen was addedDiisopropyl ethylamine (2.32 g, 18.5 mmol, 3.0 eq). The clear mixturewas stirred at ambient temperature for 12 h. The LCMS indicated thedesired product. The mixture was concentrated cooled in an ice-waterbath, further diluted with water. The white solid was filtered andwashed with water and dried in vacuum. Yield: 0.85 g (90%). ¹H NMR (400MHz, DMSO-d₆): δ 2.81-2.82 (d, 3H, J=4.5 Hz), 6.80-6.83 (m, 1H),6.94-6.95 (d, 1H, J=2.3 Hz), 7.34-7.38 (t, 2H, J=8.7 Hz), 7.44-7.47 (d,1H, J=8.8 Hz), 7.90-7.93 (m, 2H), 8.39-8.40 (d, 1H, J=4.4 Hz), 9.3 (s,1H). LCMS: (ES+) m/z=286.1 (M+H).

2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate

To a mixture of2-(4-fluorophenyl)-5-hydroxy-N-methylbenzofuran-3-carboxamide (5 g, 17.5mmol, 1 eq) in Dichloromethane (50 ml) at ambient temperature under N₂was added triethylamine (2.6 g, 26 mmol, 1.5 eq). The mixture was cooledto 0° C. and then added1,1,1-trifluoro-N-phenyl-N(trifluoromethylsulphonyl)methane sulphonamide(7.5 g, 21 mmol, 1.2 eq). The mixture was then stirred at ambienttemperature for 12 h. The reaction mixture was concentrated, dilutedwith water and extracted with EtOAc. The organic layer is further washedtwice with water, dried over sodium sulphate and concentrated to get theproduct. The product was further purified by column chromatography using230-400 silica gel and 50% EtOAc/Hexane. Yield: 6.2 g (85%). ¹H NMR (400MHz, DMSO-d₆): δ 2.83-2.84 (d, 3H, J=4.6 Hz), 7.40-7.44 (t, 2H, J=8.9Hz), 7.51-7.53 (m, 1H), 7.75-7.76 (d, 1H, J=2.52 Hz), 7.88-7.90 (d, 1H,J=8.96 Hz), 7.94-7.98 (m, 2H),) 8.51-8.52 (d, 1H, J=4.6 Hz). LCMS: (ES+)m/z=418 (M+H).

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate

To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (3.5 g, 8.4 mmol, 1 eq), boronic acid (1.95 g,10.1 mmol, 1.2 eq), in 1,4-dioxane/H₂O (5:1) was added cesium carbonate(8.21 g, 26 mmol, 3 eq) and the nitrogen gas was passed through themixture for 10 min. Then tetrakistriphenylphosphine palladium (0.97 g,0.8 mmol, 0.1 eq) was added to the reaction mixture and the nitrogen gaswas again passed through the mixture for 10 min. The above reactionmixture was heated in microwave for one hour at 90° C. About 50 ml ofwater is added to the reaction mixture and extracted with EtOAc. Theorganic layer was further washed twice with water and dried over sodiumsulphate and concentrated to get the product. The product obtained wasfurther purified by column chromatography using 40% EtOAc/Hexane aseluent. Yield; 1.5 g (40%) ¹H NMR (400 MHz, DMSO-d₆): δ 2.32 (s, 3H),2.81-2.82 (d, 3H, J=4.56 Hz), 3.85 (s, 3H), 7.39-7.43 (t, 2H, J=8.9 Hz),7.39-7.43 (m, 1H), 7.49-7.51 (d, 1H, J=8.16 Hz), 7.56 (s, 1H), 7.75-7.77(d, 1H, J=8.6), 7.83 (s, 1H), 7.89-7.91 (d, 1H, J=7.82 Hz), 7.98-8.02(m, 2H), 8.48-8.49 (d, 1H, J=4.6 Hz). LCMS: (ES+) m/z=418 (M+H).

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

To a mixture of methyl3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate(1 g, 2.4 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambienttemperature was added 5 eq. of NaOH and heated to 60° C. for 5 h. Themixture was cooled to ambient temperature and then in an ice-water bath,quenched slowly with 1.5 N HCl and then concentrated. The mixture withwhite precipitates was diluted with water and filtered to get the solid.It is further washed with water and dried in vacuum. Yield: 0.850 g(90%). This acid was also prepared by the coupling of2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate with4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid(Cs₂CO₃, (Ph₃)₄Pd, H₂O/1,4-dioxane (1:5), 90° C.) in a similar manner asdescribed. ¹H NMR (400 MHz, DMSO-d₆): δ 2.32 (s, 3H), 2.82-2.83 (d, 3H,J=4.6 Hz), 7.36-7.48 (m, 6H), 7.56-7.57 (d, 1H, J=1.44 Hz), 7.75-7.77(d, 1H, J=8.48 Hz), 7.81-8.03 (m, 2H), 8.46-8.48 (d, 1H, J=4.7 Hz),12.92 (s, 1H). LCMS: (ES+) m/z=404.0 (M+H).

1-(pyrimidin-2-yl)cyclopropanamine

2-Cyano pyrimidine (5 g, 47.6 mmol, 1 eq) was taken in a Dry THF underArgon atmosphere, then Titanium isopropoxide (17 ml, 57.1 mmol, 1.2 eq)was added slowly at ambient temperature and the reaction mixture wasstirred for 15 mins. Ethyl magnesium bromide (1M solution) in THF (107ml, 809 mmol, 2.5 eq) was added via syringe slowly at ambienttemperature, (During the addition of EtMgBr reaction mass becomesblack). Then the reaction mass was stirred for an hour. BF₃.EtO (16.7ml, 119.0 mmol, 2.5 eq) was added slowly through syringe at 0° C. Themixture was allowed to attain ambient temperature and stirred foranother one hour. 50 ml of Water was added to the reaction mixture andfiltered through the Celite and washed the bed with water and Ethylacetate. The reaction mass was basified with 10% NaOH solution (pH=9)then extracted with DCM and washed with brine solution. The requiredproduct was purified by silica gel (230-400) column chromatography usingDCM/methanol as the eluent. Yield: 2.1 g (30%). ¹H NMR (400 MHz,DMSO-d₆): δ 1.49-1.52 (m, 2H), 1.59-1.62 (m, 2H), 7.47-7.49 (t, 1H,J=4.80), 8.83-8.84 (d, 2H, J=4.80).

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.041g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq),EDC.HCl (0.086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature undernitrogen was added Diisopropylethylamine (0.16 g, 1.3 mmol). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was further purified by columnchromatography (neutral alumina) using 0.5% Methanol/DCM and finallypurified by preparative HPLC. Yield: 0.15 g (14%). ¹H NMR (400 MHz,DMSO-d₆): δ 1.33-1.36 (m, 2H), 1.59-1.61 (m, 2H), 2.31 (s, 3H),2.82-2.83 (d, 3H, J=4.8 Hz), 7.26-7.29 (t, 1H, J=4.8 Hz), 7.39-7.45 (m,4H), 7.59 (s, 1H), 7.76-7.78 (d, 1H, J=8.4 Hz), 7.86-7.87 (d, 2H, J=4.4Hz), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 8.67-8.68 (d, 2H, J=4.8 Hz),9.20 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). Column-Ascentis Express C18(5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98%MeCN-2% H₂O-10 mM NH₄COOH Flow: 1 mL/Min.

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0 3.6 100.0 0.0

-   -   RT min: 1.908, wavelength: 220 nm

HPLC Method: Column-ZORBAX C18 (4.6×150 mm-50 μm)

-   -   A: Buffer: 20 mM Ammonium acetate    -   B: Methanol    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 19.7    -   Wavelength: 220 nm, RT min: 19.7

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: ACN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 1 10 13 100 16 100

-   -   Wavelength: 254 nm, RT min: 17.2    -   Wavelength: 220 nm, RT min: 17.2

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 15.764    -   Wavelength: 220 nm, RT min: 15.764

3-fluoro-5-iodo-4-methylbenzoic acid

3-Fluoro-4-methylbenzoic acid (1 g, 6.48 mmol, 1 eq) was dissolved intrifluoromethanesulphonic acid (10 ml) and the reaction was cooled to 0°C. To the above solution N-Iodosuccinimide (1.46 g, 6.48 mmol, 1 eq) wasadded in portion and the reaction was stirred at room temperature for 14h. Later the above solution was poured into 50 ml of ice water, thesolid obtained was filtered. The solid was dissolved in ethylacetate,washed with sodiumthiosulphate solution and brine, the organic layer wasconcentrated to get the desired product as light brown solid. Yield: 1.5g (83%). ¹HNMR (400 MHz, CDCl₃): δ 2.35 (s, 3H), 7.68 (d, 1H, J=8 Hz),8.14 (s, 1H). 13.50 (br, 1H).

Methyl 3-fluoro-5-iodo-4-methylbenzoate

3-Fluoro-5-iodo-4-methylbenzoic acid (1.3 g, 4.6 mmol, 1 eq) wasdissolved in Methanol and treated with conc. Sulphuric acid (0.49 ml,9.2 mmol, 2 eq). The above solution was stirred at 50° C. for 15 h.Later on solvent was removed and to the resulting residue diethyletherwas added and the organic layer was washed with 10% sodium bicarbonatesolution and water. Finally, the organic layer was concentrated andpurified by flash silica gel column chromatography using 240-400 silicagel and using 10% EtOAc in hexane as the eluent. Yield: 1 g (77%). ¹HNMR (400 MHz CDCl₃). δ 2.39 (s, 3H), 3.90 (s, 3H), 7.64 (d, 1H, J=8 Hz),8.25 (s, 1H).

Methyl 3-fluoro-4-methyl-5-(3,3,4,4-tetramethylborolan-1-yl)benzoate

A mixture of methyl 3-fluoro-5-iodo-4-methylbenzoate (0.85 g, 2.89 mmol,1 eq), Potassium acetate (1.41 g, 14.45 mmol, 5 eq),bispinacolatodiboron (1.1 g, 4.33 mmol, 1.5 eq) and1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) (0.047 g,0.057 mmol, 0.02 eq) were dissolved in DMF and the reaction was stirredat 90° C. for 18 h. Later solvent was removed, water was added andextracted with dichloromethane, organic layer was washed with 2 M HCl,10% lithium chloride and brine. The organic layer was concentrated andhexane was added. The solid obtained was filtered and dried to get thedesired product as a white solid. Yield: 0.35 g, (41%). ¹HNMR (400 MHzCDCl₃): δ 1.35 (s, 12H), 2.49 (s, 3H), 3.90 (s, 3H), 7.69-7.71 (d, 1H,J=8 Hz), 8.18 (s, 1H).).

Methyl3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate

To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (0.5 g, 1.2 mmol, 1 eq), boronic ester (0.42g, 1.4 mmol, 1.2 eq) in 1,4-dioxane/H₂O (5:1) was added cesium carbonate(1.17 g, 3.6 mmol, 3 eq) and the nitrogen gas was passed through thesolution for 10 min. Then tetrakistriphenylphosphine palladium (0.14 g,0.12 mmol, 0.1 eq) was added to the reaction mixture and the nitrogengas was passed again through the solution for 15 min. The above reactionmixture was heated in microwave for one hour at 90° C. About 100 ml ofwater is added to the reaction mixture and extracted with EtOAc. Theorganic layer was further washed twice with water, dried andconcentrated to get the product. The product obtained was furtherpurified by column chromatography using 40% EtOAc/Hexane as the eluent.Yield: 0.5 g (40%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.23 (d, 3H, J=1.9 Hz),2.82-2.83 (d, 3H, J=4.6 Hz), 3.8 (s, 3H), 7.39-7.43 (t, 2H, J=8.4 Hz),7.39-7.43 (1H, m), 7.61 (s, 1H), 7.70-7.72 (d, 2H, J=7.2 Hz), 7.78-7.80(d, 1H, J=8.4 Hz), 7.99-8.03 (m, 2H), 8.49-8.51 (d, 1H, J=4.7 Hz). LCMS:(ES+) m/z=436 (M+H). Phenomina Luna C18 (4.6×3.0 mm-50 μm) Mphase A: 10%CH₃OH-90% H₂O-10 mM NH₄OAc Mphase B: 90% CH₃OH-10% H₂O-10 mM NH₄OAc

-   -   Flow: 5 ml/Min

Time % B 0.0 0.0 2.0 100.0 3.0 0.0

-   -   RT min: 2.135, wavelength: 220 nm

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

To a mixture of methyl3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate(0.3 g, 0.68 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambienttemperature was added 5 eq. of NaOH and heated to 60° C. for 5 h. Themixture was cooled to ambient temperature and then cooled in anice-water bath. It was acidified slowly with 1.5 N HCl and thenconcentrated. The mixture with white precipitates was diluted with waterand filtered to get the solid. It is further washed with water and driedin vacuum. Yield: 0.2 g (60%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.22 (s,3H), 2.82-2.84 (d, 3H, J=4.6 Hz), 7.39-7.43 (m, 3H,), 7.61 (s, 1H),7.66-7.70 (d, 1H, J=8.6 Hz), 7.66-7.70 (m, 1H), 7.78-7.80 (d, 1H, J=8.5Hz), 8.01-8.03 (m, 2H), 8.49-8.51 (d, 1H, J=4.76 Hz), 13.2 (s, 1H).LCMS: (ES−) m/z=420.0 (M−H) Chromolith SpeedROD C18 (4.6×3.0 mm-50 μm)Mphase A: 10% CH₃OH-90% H₂O-0.1% TFA Mphase B: 90% CH₃OH-10% H₂O-0.1%TFA.

-   -   Flow: 5 ml/Min

Time % B 0.0 0.0 2.0 100.0 3.0 0.0

-   -   RT min: 2.040, wavelength: 220 nm

1-(pyridin-2-yl)cyclopropanamine

2-Cyano pyridine (5 g, 48.0 mmol, 1 eq) was taken in dry THF under Argonatmosphere. To this mixture was added slowly Titanium isopropoxide (17ml, 57.6 mmol, 1.2 eq) at ambient temperature. The reaction mass wasstirred for 15 mins. Ethyl Magnesium Bromide (1 M solution) in THF (107ml, 809 mmol, 2.5 eq) was added via syringe slowly at room temperature,(During the addition of EtMgBr reaction mass becomes black). Then thereaction mass stirred for an hour and BF₃.Et₂O (16.7 ml, 120.0 mmol, 2.5eq) was added slowly at 0° C. After the completion of addition process,reaction mass was allowed to attain ambient temperature and the stirringcontinued for one more hour. Finally, 50 ml of water was added and thereaction mass was filtered through the Celite. The bed was furtherwashed with water and Ethyl acetate. The filtrate was basified with 10%NaOH solution (pH=9) then extracted with DCM and washed with brinesolution, the required product was purified by silica gel (60-120)column chromatography using DCM/methanol as the eluent. Yield: 1.3 g(23%). ¹H NMR (400 MHz, CDCl₃): δ 1.12-1.14 (m, 2H), 1.27-1.29 (m, 2H),2.12 (broad s, 2H), 7.03-7.07 (t, 1H), 7.33-7.35 (d, 1H), 7.60-7.62 (t,1H), 8.48-8.49 (d, 1H).

5-(3-fluoro-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.47 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine(0.075 g, 5.5 mmol, 1.2 eq) (60% purity), HOBT (0.81 g, 0.015 mmol, 1.7eq), EDC.HCl (0.16 g, 00.83 mmol, 1.8 eq) in DCM at ambient temperatureand under nitrogen was added Diisopropylethylamine (0.30 g, 2.3 mmol,5.0 eq). The clear mixture was stirred at ambient temperature for 12 h.The mixture was concentrated, diluted with water and extracted withEtOAc. The organic layer is further washed with water, dried over sodiumsulphate and concentrated. The product obtained was further purified bycolumn chromatography (neutral alumina) using 0.5% Methanol/DCM andfurther purification was done using preparative HPLC. Yield: 0.1 g(50%). ¹H NMR (400 MHz, CDCl₃): δ 1.39-1.42 (m, 2H), 1.67-1.70 (m, 2H),2.21-2.22 (d, 3H, J=2.24 Hz), 2.9-3.0 (d, 3H, J=4.88 Hz), 5.98-5.99 (s,1H), 7.06-7.09 (dd, 1H, J=5.2, 7.2 Hz), 7.18-7.36 (m, 5H), 7.53-7.62 (m,4H), 7.76 (d, 1H, J=1.36 Hz), 7.94-7.97 (m, 2H), 8.4 (s, 1H). LCMS:(ES+) m/z=538.2 (M+H). LCMS Method: Column-Atlantis dC18 (50×4.6 mm-5μm) A: 10 mM NH₄OAc; B: acetonitrile

-   -   Flow: 1 mL/Min

Time % B 0.0-3.0 30-95 3.0-4.0 95 4.0-4.5 95-30 4.5-6.0 30

-   -   RT min: 3.665, wavelength: 220 nm

HPLC Method Info: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.441    -   Wavelength: 220 nm, RT min: 10.441    -   Purity: 96%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.592    -   Wavelength: 220 nm, RT min: 9.592    -   Purity: 95.9%

Methyl 3,5-dihydroxy-4-methylbenzoate

3,5-dihydroxy-4-methylbenzoic acid (5.0 g, 29.79 mmol, 1.0 eq) and PTSA(1.13 g, 5.94 mmol, 0.2 eq) were dissolved in 50 ml of methanol, and themixture was heated to reflux for 6 h. Methanol was evaporated. Theresultant solid was washed with 10% sodium bicarbonate solution. Theaqueous solution was extracted thrice with ethyl acetate. The combinedorganic layer was dried over sodium sulphate and evaporated undervacuum. Yield: 5.25 g (96%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.98 (s, 3H),3.78 (s, 3H), 6.93 (s, 2H), 9.53 (s, 2H). LCMS: (ES+) m/z=183 (M+H)Method: Column: Phenomenex Luna C18 (4.6×30) mm, 5 micron Mphase A: 10%MeOH-90% H₂O-10 mM NH₄OAc Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc

-   -   Flow: 5 ml/min

Time (min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 0.956    -   Wavelength: 220 nm

Methyl 3-(benzyloxy)-5-hydroxy-4-methylbenzoate

Methyl 3,5-dihydroxy-4-methylbenzoate (3.5 g, 19.22 mmol, 1.0 eq) wasdissolved in 300 ml of DMF. To this solution potassium carbonate (2.52g, 18.26 mmol, 0.95 eq) was added. To this stirred suspension, benzylbromide (3.12 g, 18.26 mmol, 0.95 eq) (diluted with 50 ml of DMF) wasadded dropwise over a period of 3 h. The solution was stirred overnightat ambient temperature. Then DMF was evaporated under reduced pressure.The residue was washed with water and the product was extracted thricewith DCM. The combined DCM layers was dried over sodium sulphate andevaporated under vacuum. The required product was purified by silica gel(240-400) column chromatography using 10% ethyl acetate/hexane as theeluent. Yield: 1.6 g (30%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.07 (s, 3H),3.81 (s, 3H), 5.14 (s, 2H), 7.08 (s, 1H), 7.14 (s, 1H), 7.33-7.35 (d,1H, J=7.04 Hz), 7.39-7.42 (t, 2H, J=7.40 Hz), 7.46-7.48 (d, 2H, J=7.48Hz), 9.78 (s, 1H).

Methyl 3-(benzyloxy)-4-methyl-5-(trifluoromethylsulfonyloxy)benzoate

Methyl 3-(benzyloxy)-5-hydroxy-4-methylbenzoate (3.0 g, 11.02 mmol, 1.0eq) was dissolved in DCM followed by N-phenylbis(trifluoromethylsulphonimide) (5.9 g, 16.53 mmol, 1.5 eq). To thisstirred solution TEA (3.34 g, 33.06 mmol, 3.0 eq) was added dropwise.The resultant solution was stirred overnight at ambient temperature. Tothis reaction mass water was added and the DCM layer was separated. Theaqueous layer was extracted twice with DCM. The combined DCM layer wasdried over sodium sulphate and evaporated. The resultant oil waspurified by silica gel (60-120) column chromatography using 5% ethylacetate/hexane as the eluent. Yield: 4.0 g (80%). ¹H NMR (400 MHz,DMSO): δ 2.26 (s, 3H), 3.90 (s, 3H), 5.77 (s, 2H), 7.36-7.39 (d, 1H,J=8.20 Hz), 7.43-7.45 (t, 2H, J=7.60 Hz), 7.51 (s, 3H), 7.70 (s, 1H).

Methyl3-(benzyloxy)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To the solution of methyl3-(benzyloxy)-4-methyl-5(trifluoromethylsulfonyloxy)benzoate (1.2 g,2.96 mmol, 1.0 eq) in 1,4-dioxane was added PdCl₂(dppf) in DCM complex(242 mg, 0.296 mmol, 0.1 eq) followed by bis(pinacolato)diboron (1.5 g,5.93 mmol, 2.0 eq). To this stirred solution TEA (1.5 g, 14.83 mmol, and5.0 eq) was added. The reaction mixture was slowly heated to 110° C. andmaintained for two days in a sealed tube. 1,4-Dioxane was evaporatedunder reduced pressure. To the residue water was added and the aqueouslayer was extracted thrice with DCM. The combined DCM layer was driedover sodium sulphate and evaporated under vacuum. The crude was purifiedby silica gel (60-120) column chromatography using 1% ethylacetate/hexane as the eluent. Yield: 0.8 g (70%). ¹H NMR (400 MHz,CDCl₃): δ 1.39 (s, 12H), 2.53 (s, 3H), 3.91 (s, 3H), 5.17 (s, 2H),7.33-7.35 (d, 1H, J=7.36 Hz), 7.39-7.42 (t, 2H, J=7.50 Hz), 7.48-7.50(d, 2H, J=7.40 Hz), 7.67-7.68 (d, 1H, J=1.20 Hz), 8.00-8.01 (d, 1H,J=1.40 Hz).

Methyl3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate

To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (0.5 g, 1.2 mmol, 1 eq), boronic ester (0.55g, 1.4 mmol, 1.2 eq), in 1,4-dioxane/H₂O (5:1) was added cesiumcarbonate (1.37 g, 4.2 mmol, 3 eq) and the nitrogen gas was passedthrough the solution for 10 min. Thentetrakistriphenylphosphinepalladium (0.12 g, 0.16 mmol, 0.1 eq) wasadded to the reaction mixture and the nitrogen gas was passed again for15 min. The above reaction mixture was heated in microwave for one hourat 90° C. About 100 ml of water is added to the reaction mixture andextracted with EtOAc. The organic layer was further washed twice withwater and dried over sodium sulphate and concentrated to get theproduct. The product obtained was further purified by columnchromatography using 60-120 silica gel and 40% EtOAc/Hexane system.Yield: 0.3 g (48%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.20 (s, 3H), 2.82-2.83(d, 3H, J=4.6 Hz), 3.8 (s, 3H), 5.3 (s, 2H), 7.39-7.46 (m, 6H),7.52-7.56 (m, 4H), 7.62 (s, 1H), 7.76-7.78 (d, 1H, J=8.44 Hz), 7.99-8.03(m, 2H), 8.49-8.50 (d, 1H, J=4.52 Hz). LCMS: (ES+) m/z=524.0 (M+H).Chromolith SpeedROD C18 (4.6×3.0 mm-50 μm) Mphase A: 10% CH₃OH-90%H₂O-0.1% TFA Mphase B: 90% CH₃OH-10% H₂O-0.1% TFA

-   -   Flow: 5 ml/Min

Time % B 0.0 0.0 2.0 100.0 3.0 0.0

-   -   RT min: 2.303, wavelength: 220 nm

3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

To a mixture of methyl3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate(0.3 g, 0.57 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambienttemperature was added 5 eq. of NaOH, and the resulting mixture washeated to 60° C. for 5 h. The mixture was cooled to ambient temperatureand then cooled in ice-water bath. The reaction mixture was acidifiedwith 1.5 N HCl and then concentrated. The mixture with whiteprecipitates was diluted with water and filtered to get the solid. It isfurther washed with water and dried in vacuum. Yield: 0.2 g (70%). ¹HNMR (400 MHz, DMSO-d₆): δ 2.19 (s, 3H), 2.82-2.83 (d, 3H, J=4.56 Hz),5.27 (s, 2H), 7.34-7.46 (m, 6H), 7.50-7.55 (m, 4H), 7.60 (s, 1H),7.75-7.77 (d, 1H, J=8.44 Hz), 7.99-8.03 (m, 2H), 8.49-8.50 (d, 1H), 13.0(s, 1H). LCMS: (ES+) m/z=510 (M+H). Ascentis Express C18 (5.0×2.1-2.7μm) Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98% MeCN-2% H₂O-10mM NH₄COOH

-   -   Flow: 5 ml/Min

Time % A % B 0.0 100.0 0.0 1.5 0.0 100.0 3.2 0.0 100.0 3.6 100.0 0.0

-   -   RT min: 1.963, wavelength: 220 nm

5-(3-(benzyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.2 g, 0.40 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.064g, 0.47 mmol, 1.2 eq) (60% purity), HOBT (0.68 g, 0.012 mmol, 1.7 eq),EDC.HCl (0.064 g, 0.72 mmol, 1.8 eq) in DCM at ambient temperature undernitrogen was added Diisopropylethylamine (0.26 g, 2.0 mmol, 5.0 eq). Theclear mixture was stirred at ambient temperature for 12 h. The mixturewas concentrated, diluted with water and extracted with EtOAc. Theorganic layer was further washed with water, dried over sodium sulphateand concentrated. The product obtained was further purified by columnchromatography (neutral alumina) using 0.5% Methanol/DCM and preparativeHPLC. Yield: 0.17 g (70%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.26-1.27 (m,2H), 1.54-1.56 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (s, 3H), 5.26 (s, 2H)7.13-7.15 (q, 1H, J=4.4 Hz), 7.30-7.43 (m, 6H), 7.58 (d, 4H), 7.65-7.69(t, 2H, J=3.9 Hz), 7.74-7.79 (d, 1H, J=8.0 Hz), 7.97-8.01 (m, 2H),8.43-8.48 (dd, 2H, J=4.89 Hz), 9.186 (s, 1H). LCMS: (ES+) m/z=626 (M+H)Ascentis Express C18 (5.0×2.1-2.7 μm) Mphase A: 2% MeCN-98% H₂O-10 mMNH₄COOH Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH

-   -   Flow: 5 ml/Min

Time % A % B 0.0 100.0 0.0 1.5 0.0 100.0 3.2 0.0 100.0 3.6 100.0 0.0

2-(4-fluorophenyl)-5-(3-hydroxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-ethylbenzofuran-3-carboxamide

To a solution of3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.17 g, 0.27 mmol, 1 eq) in DCM was added BCl₃ in DCM (0.32 g, 2.7mmol, 10 eq). The clear mixture was stirred at ambient temperature forovernight. LCMS showed the desired product. The mixture was quenchedwith 10% NaHCO₃ and extracted with EtOAc. The organic layer is furtherwashed with water, dried over sodium sulphate and concentrated. Theproduct obtained was further purified by column chromatography (neutralalumina) using 0.5% Methanol/DCM and it was further purified withpreparative HPLC. Yield: 0.048 g (33%). ¹H NMR (400 MHz, DMSO-d₆): δ1.22-1.24 (m, 2H), 1.51-1.53 (m, 2H), 2.09 (s, 3H,), 2.82-2.83 (s, 3H,J=4.4 Hz), 7.12-7.15 (q, 1H), 7.30-7.32 (d, J=8 Hz, 1H), 7.37-7.43 (m,5H), 7.58 (s, 1H), 7.65-7.69 (t, 1H, J=8 Hz), 7.74-7.76 (d, 1H, J=8.8Hz), 7.97-8.01 (m, 2H), 8.43-8.48 (dd, 2H, J=16, 4.8 Hz), 9.18 (s, 1H),9.77 (s, 1H). LCMS: (ES+) m/z=536.2 (M+H). Column-Ascentis Express C18(5×2.1 mm-2.7 μm) Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98%MeCN-2% H₂O-10 mM NH₄COOH Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0 3.6 100.0 0.0

-   -   RT min: 1.862, wavelength: 220 nm

HPLC Method Info: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 2 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.255    -   Wavelength: 220 nm, RT min: 9.255    -   Purity: 95.2%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.046    -   Wavelength: 220 nm, RT min: 9.046    -   Purity: 95.8%

2-fluoro-3-iodo-4-methylbenzonitrile

A solution of 2,2,6,6-tetramethyl-4-piperidine (TMP) (550 mg, 3.93 mmol,2.1 eq) in THF (5 ml) was cooled to −78° C. under nitrogen atmosphere.N-Butyl lithium (1.6 M in hexane, 1.52 ml, 3.96 mmol, 2.1 eq) was addedslowly maintaining the temperature below −70° C. After addition, thereaction mixture was warmed to −50° C. and stirred for one hour. Theclear solution became turbid indicating the salt formation. The reactionmixture was cooled to −80° C., and a solution of2-fluoro-4-methylbenzonitrile (250 mg, 1.85 mmol, 1.0 eq) in THF (1 ml)was slowly added maintaining temperature below −70° C. The mixture wasthen warmed to −50° C. and stirred for 30 minutes. The mixture wasre-cooled to −78° C. and a saturated solution of iodine (516 mg, 2.03mmol, 1.1 eq) in THF (1 ml) was added slowly maintaining the temperaturebelow −70° C. After addition, the mixture was warmed to ambienttemperature. The reaction mixture was poured into a saturated solutionof Na₂S₂O₃ (10 ml) and stirred for 30 minutes. The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate. Theorganic layers were combined, washed with brine and dried over sodiumsulphate. The volatiles were evaporated under reduced pressure. Thecrude product was purified under silica gel (60-120) columnchromatography using 0.5% ethyl acetate/hexane as eluent. Yield: 187 mg(38%). ¹H NMR (400 MHz, CDCl₃): δ 2.55 (s, 3H), 7.13-7.15 (d, 1H, J=7.92Hz), 7.48-7.50 (t, 1H, J=4.80 Hz).

2-fluoro-3-iodo-4-methylbenzoic acid

A mixture of 2-fluoro-3-iodo-4-methylbenzonitrile (450 mg, 1.71 mmol,1.0 eq) in dioxane 2 ml and 60% sulphuric acid (2 ml) was heated at 115°C. in an oil bath for 12 h. After the mixture was cooled to roomtemperature, it was poured on to 10 g of ice. The tan solid wasfiltered, washed with water followed by ethyl acetate. The solidcollected was dried to afford 2-fluoro-3-iodo-4-methylbenzoic acid as atan crystalline solid. The filtrate was transferred to a separatoryfunnel. The ethyl acetate layer was separated, washed with brine, driedover sodium sulphate and concentrated to afford additional2-fluoro-3-iodo-4-methylbenzoic acid. Yield: 450 mg (93%). ¹H NMR (400MHz, DMSO-d₆): δ 2.48 (s, 3H), 7.27-7.29 (d, 1H, J=8.00 Hz), 7.74-7.78(t, 1H, J=7.82 Hz), 13.2 (b, 1H).

Methyl 2-fluoro-3-iodo-4-methylbenzoate

To the solution of 2-fluoro-3-iodo-4-methylbenzoic acid (450 mg, 1.6mmol, 1.0 eq) in methanol (5 ml), catalytic amount of conc.HCl (0.1 ml)was added. The resultant solution was heated to reflux at 80° C. forovernight. Methanol was evaporated. To this residue, water was added andthe aqueous layer was extracted thrice with ethyl acetate. The combinedethyl acetate extracts were dried over sodium sulphate, filtered andevaporated to afford methyl 2-fluoro-3-iodo-4-methylbenzoate. Yield: 450mg (95%). ¹H NMR (400 MHz, DMSO): δ 2.49 (s, 3H), 3.85 (s, 3H),7.30-7.32 (d, 1H, J=7.84 Hz), 7.76-7.80 (t, 1H, J=7.82 Hz). LCMS: (ES+)m/z=295 (M+H).

Methyl2-fluoro-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To the solution of methyl 2-fluoro-3-iodo-4-methylbenzoate (1.1 g, 3.74mmol, 1.0 eq) in DMSO was added[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (305 mg, 0.37mmol, 0.1 eq) followed by bis(pinacolato)diboron (1.9 g, 7.48 mmol, 2.0eq). To this solution potassium acetate (1.83 g, 18.7 mmol, 5.0 eq) wasadded and nitrogen gas was passed through for 10 minutes. The resultantsolution was irradiated with microwave at 80° C. for 40 minutes.Reaction mixture was quenched with brine solution. The aqueous layer wasextracted thrice with ethyl acetate. The combined organic layer wasdried over sodium sulphate and the clear ethyl acetate layer wasevaporated under vacuum. The crude was purified by silica gel (60-120)column chromatography using 1% ethyl acetate/hexane as eluent. Yield:400 mg (36%). ¹H NMR (400 MHz, CDCl₃): δ 1.38 (s, 12H), 2.46 (s, 3H),3.89 (s, 3H), 6.98-7.00 (d, 1H, J=7.84 Hz), 7.81-7.85 (t, 1H, J=7.82Hz). LCMS: (ES+) m/z=295 (M+H).

Methyl2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate

To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (0.4 g, 0.96 mmol, 1 eq), boronic ester (0.366g, 1.24 mmol, 1.3 eq), in 1,4-dioxane/H₂O (5:1) was added cesiumcarbonate (0.938 g, 2.87 mmol, 3 eq) and the nitrogen gas was passedthrough for 10 min. Then tetrakistriphenylphosphine palladium (0.111 g,0.095 mmol, 0.1 eq) was added to the reaction mixture and nitrogen gaswas again passed through the mixture for 15 min. The above reactionmixture was heated in microwave for one hour at 90° C. About 100 ml ofwater is added to the reaction mixture and extracted with EtOAc. Theorganic layer was further washed twice with water and dried over sodiumsulphate, concentrated to get the product. The product obtained wasfurther purified by column chromatography using 60-120 silica gel and25% EtOAc/Hexane as eluent. Yield: 0.320 g (76%). ¹H NMR (400 MHz,DMSO-d₆): δ 2.19 (s, 3H), 2.81-2.82 (d, 3H, J=4.64 Hz), 3.85 (s, 3H),7.31-7.34 (d, 2H, J=8.28 Hz), 7.39-7.44 (t, 2H, J=8.90 Hz), 7.54 (s,1H), 7.79-7.85 (m, 2H), 7.97-8.01 (m, 2H), 8.45-8.46 (d, 1H, J=4.32 HzLCMS: (ES+) m/z=436 (M+H). Method: Column: Chromolith SpeedRod C18(4.6×30)mm, 5 micron Mphase A: 10% MeOH-90% H2O-0.1% TFA Mphase B: 90%MeOH-10% H2O-0.1% TFA

-   -   Flow: 5 ml/min

Time(min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 2.034    -   Wavelength: 220 nm

2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

To a mixture of methyl3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate(0.320 g, 1 eq) in a 1:1 mixture of MeOH/THF, 1 M solution of NaOH(0.088 g, 2.20 mmol, 3.0 eq) was added and heated to 90° C. for 3 h. Themixture was cooled to ambient temperature and then in an ice-water bath.It was acidified with 1.5 N HCl and then volatiles were evaporated. Themixture with white precipitate was diluted with water and filtered toget the product. It was further washed with water and dried in vacuum.Yield: 0.220 g (71%). ¹H NMR (400 MHz, DMSO-d₆): δ 2.17 (s, 3H),2.81-2.82 (d, 3H, J=4.60 Hz), 7.28-7.33 (m, 2H, J=4.33 Hz), 7.39-7.44(m, 2H, J=8.88 Hz), 7.53 (d, 1H, J=1.24 Hz), 7.78-7.83 (m, 2H, J=5.93Hz), 7.97-8.01 (m, 2H), 8.45-8.47 (d, 1H, J=4.60 Hz), 13.13 (s, 1H).LCMS: (ES+) m/z=422.0 (M+H). Method: Column: Chromolith SpeedRod C18(4.6×30)mm, 5 micron Mphase A: 10% MeOH-90% H2O-0.1% TFA Mphase B: 90%MeOH-10% H2O-0.1% TFA Flow: 5 ml/min

Time(min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 1.961    -   Wavelength: 220 nm

5-(2-fluoro-6-methyl-3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To the solution of2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.1 g, 0.273 mmol, 1.0 eq) in DMF (5.0 ml),1-(pyridin-2-yl)cyclopropanamine (0.038 g, 0.285 mmol, 1.2 eq), TBTU(0.130 g, 0.403 mmol, 1.7 eq) and DIPEA (0.154 g, 1.187 mmol, 5.0 eq)were added. Mixture was stirred at ambient temperature for 12 h undernitrogen atmosphere. DMF was concentrated and to this residue water wasadded and extracted with ethyl acetate. The combined organic layer wasdried over sodium sulphate and ethyl acetate was evaporated. The crudewas purified by preparative TLC eluted with hexane/EtOAc (5:5). Theproduct was further purified by recrystallization with DCM and hexane.Yield: 0.045 g (39%). ¹H NMR (400 MHz, DMSO-d₆): δ 1.23-1.25 (m, 2H),1.51-1.54 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (d, 3H, J=4.0 Hz), 7.13-7.15(t, 1H, J=3.78 Hz), 7.27-7.29 (d, 1H, J=8.00 Hz), 7.33-7.35 (d, 1H,J=4.26 Hz), 7.39-7.44 (m, 3H, J=5.26 Hz), 7.56-7.60 (t, 2H, J=7.56 Hz),7.68-7.72 (m, 1H), 7.80-7.82 (d, 1H, J=8.44 Hz), 7.96-8.00 (m, 2H),8.43-8.49 (m, 2H), 9.12 (s, 1H). LCMS: (ES+) m/z=538.0 (M+H). Method:Column: Chromolith SpeedRod C18 (4.6×30) mm, 5 micron Mphase A: 10%MeOH-90% H2O-0.1% TFA Mphase B: 90% MeOH-10% H2O-0.1% TFA Flow: 5 ml/min

Time (min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 1.813    -   Wavelength: 220 nm

HPLC Method:

COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 3 10 14 100 17 100

-   -   Wavelength: 254 nm, RT min: 10.566 (Purity: 98.287%)    -   Wavelength: 220 nm, RT min: 10.041 (Purity: 97.3%)

COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.041 (Purity: 98.3%)    -   Wavelength: 220 nm, RT min: 10.041 (Purity: 97.3%)

2-methyloxazole-4-carbonitrile

Ethylacetimidate hydrochloride (25 g, 340 mmol, 1 eq) andaminoacetonitrile (38.5 g, 410 mmol, 1.2 eq) were suspended indichloromethane (300 ml) at room temperature. Triethylamine (148.4 ml,380 mmol, 1.1 eq) was added dropwise over 1 h. After the completion ofaddition, the reaction mixture was cooled to 0° C., water (125 ml) wasadded, organic layer was separated and the aq. layer was extracted with50 ml of dichloromethane. The combined dichloromethane mixture wasconcentrated to 50 ml. Diethyl ether (500 ml) was added to thissolution, which was then cooled to 0° C. To the above solutionethylformate (13.93 g, 190 mmol, 0.55 eq) was added followed by theaddition of Potassium tert-butoxide (20.6 g, 172 mmol, 0.51 eq). Thereaction was allowed to stir at room temperature for 90 minutes and at50° C. for 90 minutes. Chlorotrimethylsilane (56.5 g, 520 mmol, 1.5 eq)was added at reflux condition and the reaction was stirred at 50° C. for5 h. Later water was added and the product was extracted withdichloromethane and the organic layer was washed with water and purifiedby column chromatography yielding product as colorless oil. Yield: 6 g(16%) overall yield. ¹HNMR (400 MHz, DMSO-d₆): δ 2.5 (s, 3H), 8.07 (s,1H).

1-(2-methyloxazol-4-yl)cyclopropanamine

2-Methyloxazole-4-carbonitrile (5 g, 46.1 mmol, 1 eq) was dissolved indry THF at room temperature, and to which titanium(IV) isopropoxide (16ml, 655 mmol, 1.2 eq) was added dropwise over a period of 15 minutes.The resulting mixture was stirred for 10 min and ethyl magnesium bromide(85 ml, 17 volumes) was added slowly dropwise at ambient temperature andthe reaction was stirred for 1 h. Later BF₃.etherate (16.7 ml, 115 mmol,2.5 eq) was added slowly at ambient temperature and the above solutionwas stirred at ambient temperature for 3 h. Finally water was added andthe pH was brought to 10 using 10% sodium hydroxide solution. Thereaction mixture was extracted with dichloromethane, concentrated andpurified by combiflash chromotagraphy. Yield: 1.5 g (20%). ¹HNMR (400MHz, DMSO-d₆): δ 0.93 (m, 2H), 1.00 (m, 2H), 1.98 (br s, 2H), 2.39 (s,3H), 7.33 (s, 1H). LCMS: (ES+) m/z=138.9 (M+H).

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.15 g, 0.37 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine(0.066 g, 0.47, 1.2 eq), HOBT (0.092 g, 0.68 mmol, 1.7 eq), EDC.HCl(0.14 g, 0.73 mmol, 1.8 eq) in DCM at ambient temperature under nitrogenwas added Diisopropylethylamine (0.26 g, 2.2 mmol, 5.0 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer is further washed with water, dried over sodium sulphate andconcentrated. The product obtained was further purified by columnchromatography (neutral alumina) using 0.5% Methanol/DCM as an eluentfollowed by preparative HPLC. Yield: 0.02 g (20%). ¹H NMR (400 MHz,DMSO-d₆): δ 1.10-1.13 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.33 (s,3H), 2.81-2.82 (d, 3H, J=4.6 Hz), 7.38-7.43 (m, 4H), 7.57 (s, 1H), 7.61(s, 1H), 7.75-7.71 (d, 1H, J=8.4 Hz), 7.80-7.81 (s and m, 2H), 7.97-8.01(m, 2H), 8.47-8.48 (d, 1H, J=4.76 Hz), 9.1 (s, 1H). LCMS: (ES+)m/z=524.2 (M+H). LCMS Method: Chromolith SpeedROD C18 (4.6×3.0 mm-50 μm)Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98% MeCN-2% H₂O-10 mMNH₄COOH Flow-1 mL/Min

Time % B 0.0 0.0 2.0 100.0 3.0 100.0

-   -   RT min: 2.018, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150) mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 4 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.757    -   Wavelength: 220 nm, RT min: 10.757    -   Purity: 96.7%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.993    -   Wavelength: 220 nm, RT min: 9.993    -   Purity: 96.7%

1-(pyrimidin-5-yl)cyclopropanamine

5-Cyano pyrimidine (5 g, 47.6 mmol, 1 eq) was taken in a Dry THF underArgon atmosphere, then Titanium isopropoxide (17 ml, 57.1 mmol, 1.2 eq)was added slowly at ambient temperature and the resulting mass wasstirred for 15 mins. To the above stirred solution was added Ethylmagnesium bromide (1 M solution in THF, 107 ml, 809.3 mmol, 2.5 eq)slowly via syringe at ambient temperature. (During the addition ofEtMgBr reaction mass turned black). Then the reaction mass was stirredfor an hour, BF₃.EtO (16.7 ml, 119.0 mmol, 2.5 eq) was added slowlythrough syringe at 0° C. Then the reaction was allowed to attain ambienttemperature and the stirring was continued for another one hour. Finallythe reaction was quenched by adding 50 ml of water and the reaction masswas passed through Celite and the bed was washed with water and Ethylacetate. The filtrate was basified with 10% NaOH solution (pH=9) andthen extracted with DCM and washed with brine solution. The requiredproduct was purified by silica gel (60-120) column chromatography usingDCM/methanol as the eluent. Yield: 0.1 g (5%) ¹H NMR (400 MHz, DMSO-d₆):1.04-1.08 (q, 2H, J=3.96 Hz), 1.18-1.25 (q, 2H, J=3.96 Hz), 8.26 (d,2H), 9.05 (s, 1H). LCMS: (ES+) m/z=136 (M+H).

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-5-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.041g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq),EDC.HCl (0086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature undernitrogen was added Diisopropylethylamine (0.162 g, 1.2 mmol, 5.0 eq).The clear mixture was stirred at ambient temperature for overnight. Themixture was concentrated, diluted with water and extracted with EtOAc.The organic layer is further washed with water, dried over sodiumsulphate and concentrated. The product obtained was further purified bycolumn chromatography (neutral alumina) using 0.5% Methanol/DCM andfinally it was purified by preparative HPLC. Yield: 0.02 g (20%). ¹H NMR(400 MHz, DMSO-d₆): δ 1.34-1.35 (m, 2H), 1.41-1.42 (m, 2H), 2.29 (s,3H), 2.81-2.82 (d, 3H, J=4.56 Hz), 738-7.45 (m, 4H), 7.58 (d, 1H, J=0.96Hz), 7.75 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.83 (m, 1H), 7.98-8.01 (m,2H), 8.46-8.47 (d, 1H, J=4.6 Hz), 8.64 (s, 2H), 9.01 (s, 1H), 9.31 (s,1H). LCMS: (ES+) m/z=521.2 (M+H). LCMS Method: Column-Ascentis ExpressC18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H₂O-10 mM NH₄COOH Mphase B:98% ACN-2% H₂O-10 mM NH₄COOH Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0 3.6 100.0 0.0

-   -   RT min: 1.825, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.061    -   Wavelength: 220 nm, RT min: 10.061    -   Purity: 92.3%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.542    -   Wavelength: 220 nm, RT min: 9.542    -   Purity: 92.5%

1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine

Ethyl magnesium bromide (2.5 mol, 1 M in ether) was added at −78° C. toa solution of a 1-methyl-1H-pyrazole-3-carbonitrile (0.5 g, 1 mmol) andTi(Oi-Pr)₄ (1.1 mmol) in Et₂O (5 mL). The yellow solution was stirredfor 10 min. After the solution was warmed to ambient temperature (1 h),BF₃.OEt₂ (2 mmol) was added. After the mixture was stirred for 1 h, 1 NHCl and ether were added. NaOH (10%) was added to the resulting twoclear phases and the mixture was extracted with ether. The combinedether layers were dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel (Et₂O). ¹H NMR (400 MHz, CDCl₃): δ 0.94-1.05 (m, 4H), 2.32(s, 2H), 3.83 (s, 3H), 5.92 (d, 1H), 7.23-7.24 (d, 1H). LCMS: (ES+) m/zobserved 137.7.

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.15 g, 0.37 mmol, 1 eq),1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2eq), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0.086 g, 0.44 mmol, 1.8eq) in DCM at ambient temperature under nitrogen was addeddiisopropylethylamine (0.16 g, 1.2 mmol, 5.0 eq). The clear mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic layer wasfurther washed with water, dried over sodium sulphate and concentrated.The product obtained was further purified by column chromatography(neutral alumina) using 0.5% Methanol/DCM and finally by preparativeHPLC. Yield: 0.06 g (40%) ¹H NMR (400 MHz, DMSO-d₆): δ 1.12-1.16 (m,2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.82-2.83 (d, 3H, J=4.64 Hz), 3.37(s, 3H), 5.9-6.0 (d, 1H, J=2.12 Hz), 7.39-7.48 (m, 5H), 7.58 (d, 1H,J=1.68 Hz), 7.75-7.77 (d, 1H, J=9.7 Hz), 7.81-7.83 (t, 2H, J=2.87 Hz),7.98-8.46 (m, 2H), 8.47-8.48 (d, 1H, J=4.52 Hz), 9.14 (s, 1H). LCMS:(ES+) m/z=523.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1mm-2.7 μm) Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98% MeCN-2%H₂O-10 mM NH₄COOH Flow: 1 ML/Min

Time % A % B 0.0 100.0 0.0 1.0 70.0 30.0 2.5 0.0 100.0 4.0 0.0 100.0

-   -   RT min: 1.882, wavelength: 220 nm

HPLC Method Info: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.999    -   Wavelength: 220 nm, RT min: 16.999    -   Purity: 96%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 15.556    -   Wavelength: 220 nm, RT min: 15.556    -   Purity: 97%

Methyl 2-methoxy-4-methylbenzoate

Methyl 2-methoxy-4-methylbenzoic acid (1.5 g, 9.0 mmol, 1 eq) wasdissolved in DMF, methyl iodide (0.86 ml, 13.5 mmol, 1.5 eq) was addedto it followed by the addition of potassium carbonate (3.11 g, 22.5mmol, 2.5 eq). The above mixture was stirred at room temperature for 12h. Finally, the reaction mixture was passed through celite. The filtratewas evaporated and water was added and the product was extracted withethyl acetate. The organic layer was washed with water and concentrated.Yield: 1.6 g (98%). ¹HNMR (400 MHz, CDCl₃): δ 2.31 (s, 3H), 3.86 (s,3H), 3.89 (s, 3H), 6.77 (s, 1H), 6.79 (d, 1H), 7.14 (d, 1H).

Methyl 5-iodo-2-methoxy-4-methylbenzoate

Methyl 2-methoxy-4-methylbenzoate (1.5 g, 8.32 mmol, 1 eq) was dissolvedin methanol. To this solution was added dropwise iodine monochloride(6.75 g, 41.6 mmol, 5 eq) in methanol at room temperature. The reactionmixture was heated at 50° C. for 15 h. Finally, methanol wasconcentrated, diluted with water and extracted with ethyl acetate. Theorganic layer was washed with 0.1 N HCl (50 ml), water (100 ml) andbrine solution (100 ml). The product was purified by columnchromatography using 60-120 silica gel and using 5% ethyl acetate/hexaneas eluent. Yield: 1.7 g (80%). ¹HNMR (400 MHz, CDCl₃): δ 2.44 (s, 3H),3.86 (s, 3H), 3.88 (s, 3H), 6.86 (s, 1H), 8.20 (s, 1H). LCMS: (ES+)m/z=307.0 (M+H).

Methyl2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Methyl 5-iodo-2-methoxy-4-methylbenzoate (1.5 g, 4.9 mmol, 1 eq),Bispinacolatodiboron (1.49 g, 5.8 mmol, 1.2 eq), potassium acetate (1.44g, 14.7 mmol, 3 eq) and Pd(dppf)Cl₂ (0.4 g, 0.49 mmol, 0.1 eq) weredissolved in DMF. Nitrogen gas was passed through the mixture for 10minutes and the mixture was stirred at 90° C. for 14 hours. Later thesolution was passed through celite. The filtrate was evaporated anddiluted with water and extracted with ethyl acetate and purified bycolumn chromatography using 60-120 silica gel and using 20% ethylacetate/hexane as eluent. Yield: 1.2 g (80%). ¹HNMR (400 MHz, CDCl₃): δ1.33 (s, 12H), 2.56 (s, 3H), 3.86 (s, 3H), 3.91 (s, 3H), 6.75 (s, 1H),8.21 (s, 1H). LCMS: (ES+) m/z=307.2 (M+H).

Methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate

Methyl-2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(1.2 g, 3.92 mmol, 1 eq),2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate(1.6 g, 3.92 mmol, 1 eq), Cesium carbonate (3.8 g, 11.7 mmol, 3 eq) andTetrakis triphenylphosphinepalladium (0.13 g, 0.11 mmol, 0.03 eq) weredissolved in 1,4-dioxane/water and the above solution was stirred at 90°C. for 10 h. Then the reaction mixture was diluted with water andproduct was extracted with ethyl acetate and purified by combiflashchromatography using 40% ethyl acetate/hexane as eluent. Yield: 0.95 g(55%). ¹HNMR (400 MHz, DMSO-d₆): δ 2.3 (s, 3H), 2.82 (d, J=4.6 Hz, 3H),3.78 (s, 3H), 3.88 (s, 3H), 7.15 (s, 1H), 7.51 (s, 1H), 7.64 (m, 2H),7.65 (m, 2H), 7.74 (d, 1H, J=8.48 Hz), 8.00-8.01 (m, 2H), 8.48 (d, 1H).LCMS: (ES+) m/z=448 (M+H).

5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid

Methyl5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate(0.9 g, 2 mmol, 1 eq) and sodium hydroxide (0.4 g, 10 mmol, 5 eq) weredissolved in methanol/water (20/5 ml) and the reaction was stirred at50° C. for 10 h. Then the reaction mixture was concentrated and dilutedwith water and the pH of the solution was brought to 3 by using ConcHCl. The solid obtained was filtered and dried overnight. Yield: 0.72 g(82%). ¹HNMR (400 MHz, DMSO-d₆): δ 2.29 (s, 3H), 2.87 (d, 3H), 3.87 (s,3H), 7.09 (s, 1H), 7.40-7.60 (m, 3H), 7.57 (m, 2H), 7.65 (d, 1H, J=8.74Hz), 7.98-8.01 (m, 2H), 8.46 (q, 1H, J=4.40 Hz), 12.5 (br s, 1H). LCMS:(ES+) m/z=434 (M+H) Method: Mphase A: water Mphase B: 0.1% acetone inwater Flow-2 mL/Min

Time % B 0-20 100

-   -   RT min: 1.741    -   Wavelength: 220 nm

Additional LCMS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeO{tilde over (H)}90% H₂Õ0.1% TFA, Solvent B=90% MeO{tilde over (H)}10%H₂Õ0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=434.10, HPLC R_(t)=1.653 min.

2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-2-yl)cyclopropanamine (0.074g, 0.55 mmol, 1.2 eq), HOBT (0.105 g, 0.77 mmol, 1.7 eq), EDC.HCl(0.0.158 g, 0.82 mmol, 1.8 eq), in DCM at ambient temperature and undernitrogen atmosphere was added diisopropylethylamine (0.297 g, 2.2 mmol,5.0 eq). The clear mixture was stirred at ambient temperature for 12 h.The mixture was concentrated, diluted with water and extracted withEtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was furtherpurified by column chromatography (neutral alumina) using 0.5%Methanol/DCM and preparative HPLC. Yield: 0.055 g (45%). ¹HNMR (400 MHz,DMSO-d₆): δ 1.43-1.44 (m, 2H), 1.59-1.62 (m, 2H), 2.31 (s, 3H),2.81-2.82 (d, 3H, J=4.56 Hz), 4.01 (s, 3H), 7.17 (s, 1H), 7.26-7.29 (t,1H, J=4.8 Hz), 7.33-7.36 (dd, 1H, J=8.4, 4 Hz), 7.38-7.43 (t, 2H, J=8.8Hz), 7.50-7.51 (d, 1H, J=1.6 Hz), 7.72-7.76 (m, 2H), 7.97-8.01 (m, 2H),8.48-8.49 (d, 1H, J=4.4 Hz), 8.7 (d, 2H, J=4.8 Hz), 8.87 (s, 1H). LCMS:(ES+) m/z=551.2 (M+H) Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98% MeCN-2% H₂O-10 mMNH₄COOH Flow: 1 mL/Min

Time % A % B 0.0 100.0 0.0 1.0 70.0 30.0 2.5 0.0 100.0 4.0 0.0 100.0

-   -   RT min: 1.946, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.209    -   Wavelength: 220 nm, RT min: 18.209    -   Purity: 99.4%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.549    -   Wavelength: 220 nm, RT min: 16.549    -   Purity: 99.5%

2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(2-methyloxazol-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.15 g, 0.34 mmol, 1 eq), 1-(2-methyloxazol-4-yl)cyclopropanamine(0.047 g, 0.34 mmol, 1 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT(0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) weredissolved in dichloromethane and the reaction was stirred at roomtemperature for 14 h. The reaction was diluted with water and theproduct was extracted with dichloromethane and purified by preparativeHPLC yielding the desired product. Yield: 47 mg (25%) ¹H NMR (400 MHz,DMSO-d₆): δ 1.12-1.15 (m, 2H), 1.21-1.24 (m, 2H), 2.29 (s, 3H), 2.34 (s,3H), 2.81-2.82 (d, 3H, J=4.60 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.31-7.32(m, 1H), 7.34-7.40 (t, 2H, J=3.21 Hz), 7.56 (s, 1H), 7.61 (s, 1H), 7.71(s, 1H), 7.73 (s, 1H), 7.97-8.01 (m, 2H), 8.46-8.48 (m, 1H), 8.67 (s,1H). LCMS: (ES+) m/z=554.2 (M+H).: Column-Ascentis Express C18 (5×2.1mm-2.7 μm) Mphase A: 2% ACN-98% H₂O-10 mM NH₄COOH Mphase B: 98% ACN-2%H₂O-10 mM NH₄COOH

-   -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.0 70.0 30.0 2.5 0.0 100.0 4.0 0.0 100.0

-   -   RT min: 1.964, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.403    -   Wavelength: 220 nm, RT min: 11.402    -   Purity: 98.8%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.588    -   Wavelength: 220 nm, RT min: 10.588    -   Purity: 98.96%

2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(1-methyl-1H-pyrazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.15 g, 0.35 mmol, 1 eq),1-(1-methyl-1H-pyrazol-3-yl)cyclopropanamine (0.058 g, 0.42 mmol, 1.2eq), HOBT (0.08 g, 0.069 mmol, 1.7 eq), EDC.HCl (0.073 g, 0.014 mmol,1.8 eq), in DCM at ambient temperature under nitrogen was addedDiisopropylethylamine (0.297 g, 2.2 mmol, 5.0 eq). The clear mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic layer isfurther washed with water, dried over sodium sulphate and concentrated.The product obtained was further purified by column chromatography(neutral alumina) using 0.5% Methanol/DCM and the final purification wasdone by preparative HPLC. Yield: 0.06 g (45%) ¹H NMR (400 MHz, DMSO-d₆):δ 1.18-1.20 (m, 4H), 2.29 (s, 3H), 2.81-2.82 (d, 3H, J=4.64 Hz), 3.73(s, 3H), 3.96 (s, 3H), 6.06-6.07 (d, 1H, J=2.4 Hz), 7.12 (s, 1H),7.32-7.34 (dd, 1H, J=8.4, 1.6 Hz), 7.38.-7.42 (t, 2H, J=8.8 Hz),7.48.-7.49 (d, 2H, J=2.34 Hz), 7.59 (s, 1H), 7.71-7.73 (d, 1H, J=8.4Hz), 7.97-7.97-8.01 (m, 2H), 8.47-8.48 (d, 1H, J=4.8 Hz), 8.69 (s, 1H).LCMS: (ES+) m/z=553.2 (M+H).: Column-Ascentis Express C18 (5×2.1 mm-2.7μm) Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH Mphase B: 98% MeCN-2% H₂O-10mM NH₄COOH Flow: 1 mL/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.937, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.289    -   Wavelength: 220 nm, RT min: 11.289    -   Purity: 99.3%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.548    -   Wavelength: 220 nm, RT min: 10.548    -   Purity: 99.5%

1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine

1-Methyl-1H-imidazole-4-carbonitrile (0.5 g, 4.6 mmol, 1 eq) wasdissolved in THF, and to which titanium isopropoxide (1.6 g, 5.6 mmol,2.5 eq) was added dropwise over 15 minutes. The mixture was stirred for15 minutes at room temperature, and then ethyl magnesium bromide (1.6 g,11.5 mmol, 2.5 eq) was added at room temperature over 15 minutes. Thereaction mixture was stirred for 1 h. BF₃ etherate (0.8 g, 5.6 mmol, 2.2eq) was added and the mixture stirred at room temperature for 1 h. 1 NNaOH solution was added to the mixture to bring the pH to 9-10. Reactionmass was filtered through celite and the filtrate washed with DCM. Theorganic mixture was concentrated and the residue purified by flashchromatography on silica gel using 10% chloroform/methanol. Yield: 0.6 g¹H NMR (400 MHz, CDCl₃): δ 0.97 (t, J=3.4 Hz, 2H), 1.00 (t, J=3.4 Hz,2H), 3.63 (s, 3H), 7.28 (s, 1H), 7.31 (s, 1H). LCMS: (ES+) m/z=138.2(M+H).

2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(1-methyl-1H-imidazol-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

5-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.07g, 1.1 eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA(0.19 ml, 3 eq) were dissolved in dichloromethane and the above solutionwas stirred at room temperature for 18 h. Later water was added andorganic layer was separated. The organic layer was washed with water andthe crude product was purified by Prep. HPLC. Yield: 24.69 mg (10%)¹HNMR (400 MHz, CDCl₃): δ 1.39 (s, 4H), 2.30 (s, 3H), 2.99-3.01 (d,J=4.6 Hz, 3H), 3.81 (s, 3H), 4.04 (s, 3H), 5.90 (s, 1H), 6.87 (s, 1H),7.16-7.25 (m, 3H), 7.24 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.65 (s, 1H),7.98-7.99 (m, 3H), 8.29 (s, 1H), 8.95 (s, 1H). LCMS: (ES+) m/z=553.2(M+H). Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A:2% ACN-98% H₂O-10 mM NH₄COOH Mphase B: 98% ACN-2% H₂O-10 mM NH₄COOHFlow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.854    -   Wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 11.685    -   Wavelength: 220 nm, RT min: 11.685    -   Purity: 99.1%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 13.396    -   Wavelength: 220 nm, RT min: 13.396    -   Purity: 96.5%

Preparative HPLC Method:

-   -   Column: Symmetry C18 (19×250×10μ)    -   Mobile Phase: 0.1% TFA (A), MeCN (B)    -   Gradient:

Time Flow A B 0 15 ml/min 95 5 10 15 ml/min 55 45

-   -   RT: 10.5 min

1-(5-methylisoxazol-3-yl)cyclopropanamine

5-Methylisoxazole-3-carbonitrile (1.0 g, 1 mmol) was dissolved in THF.Ti (Oi-Pr) 4 (1.2 mmol) was added dropwise over a period of 5-10 min andthe reaction mixture was stirred at r.t for 15 min. It was then cooleddown to 0° C. and EtMgBr (2.5 mmol) was added dropwise over a period of10-15 min. It was stirred at 0° C. for 15 min. and then stirred at rtfor 1 hr. The mixture was cooled again to 0° C. and BF₃OEt₂ (2 mmol) wasadded dropwise over a period of 5-10 min at 0° C. After the mixture wasstirred for 10 min at 0° C. and 1 hr at rt, 1 N NaOH was added at 0° C.DCM was added to the reaction mixture which was then stirred for 5-10min. This alkaline solution was filtered through celite and washed withDCM. The organic layer was concentrated and residue purified by flashchromatography on silica gel using 10% chloroform/methanol. Yield: 0.6 g¹H NMR (400 MHz, CDCl₃): δ 0.96-1.05 (m, 4H), 2.36 (s, 3H), 5.59 (s,1H). LCMS: (ES+) m/z observed 138.7.

2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methylisoxazol-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.15 g, 0.37 mmol, 1 eq), amine (0.06 g, 0.43 mmol, 1.2 eq), HOBT(0.084 g, 0.62 mmol, 1.7 eq), EDC.HCl (0.127 g, 0.087 mmol, 1.8 eq) inDCM at ambient temperature under nitrogen was addedDiisopropylethylamine (0.239 g, 1.8 mmol, 5.0 eq). The clear mixture wasstirred at ambient temperature for 12 h. LCMS showed the desiredproduct. The mixture was concentrated, diluted with water and extractedwith EtOAc. The organic layer is further washed with water, dried oversodium sulphate, filtered and then concentrated. The product obtainedwas further purified by column chromatography (neutral alumina) using0.5% Methanol/DCM and preparative HPLC. Yield: 0.03 g (20%). ¹H NMR (400MHz, DMSO-d₆): δ 1.24-1.29 (m, 4H), 2.29 (s, 3H), 2.32 (s, 3H),2.81-2.82 (d, 3H, J=4.6 Hz), 6.05 (s, 1H), 7.38-7.44 (m, 4H), 7.57 (d,1H, J=1.6 Hz), 7.75-7.82 (m, 3H), 7.97-8.0 (m, 2H), 8.46-8.47 (m, 1H),9.24 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H). LCMS Method: Column-AscentisExpress C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H₂O-10 mM NH₄COOHMphase B: 98% ACN-2% H₂O-10 mM NH₄COOH Flow: 1 mL/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.966, wavelength: 220 nm

HPLC Method: Column-ATLANTIS T3 (4.6×150 mm-5.0 μm)

-   -   A: Buffer: 20 mM Ammonium acetate in Water    -   B: MeCN    -   FLOW: 1 ml/min

Time B % 20 0 35 5 35 30 100 35 100 40

-   -   Wavelength: 254 nm, RT min: 15.155    -   Wavelength: 220 nm, RT min: 15.155

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: ACN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 18.678    -   Wavelength: 220 nm, RT min: 18.678    -   Purity: 99.4%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:ACN (95:5)    -   Mobile Phase B: ACN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 17.135    -   Wavelength: 220 nm, RT min: 17.135    -   Purity: 99.5%

5-methylthiazole-2-carbaldehyde

To a solution of BuLi (5 mmol) in ether at −78° C. was added dropwise asolution of 5-methylthiazole (5 mol) in ether at −78° C. for 1.5 hours.A solution of DMF (5 mmol) in ether was added at once and the reactionwas allowed to warm to room temperature and stirred overnight. Ice wasadded to the mixture followed by the slow addition of 4 N HCl. Themixture was extracted with ether. The aq. layer was bought to pH 7.5with solid NaHCO₃ and extracted with ether. The combined etherealextracts was dried, filtered and concentrated to get crude residue,which was purified by flash chromatography on silica gel using 10%EtOAc/Hexane. Yield: 6 g ¹H NMR (400 MHz, CDCl₃): δ 2.56 (s, 3H), 7.79(s, 1H), 9.90 (s, 1H). LCMS: (ES+) m/z=128 (M+H).

5-methylthiazole-2-carbaldehyde oxime

To a solution of 5-methylthiazole-2-carbaldehyde (4.8 mmol) in DCM wasadded pyridine (4.8 mmol) and HONH₂.HCl (4.8 mmol). The reaction mixturewas stirred at ambient temperature for 12 hours, then diluted with DCMand extracted with water. The organic extract was dried, filtered andconcentrated to obtain crude oxime. Yield: 6 g; LCMS: (ES+) m/z=143(M+H).

5-methylthiazole-2-carbonitrile

5-Methylthiazole-2-carbaldehyde oxime (4.2 mmol) was dissolved in DCMand added with CDI (4.3 mmol) portionwise. The reaction mixture and stirat rt overnight, and then added with water. The mixture was extractedwith DCM, and the organic layer was dried and concentrated to get thecrude residue, which was purified by flash chromatography on silica gelusing 10% EtOAc/Hexane. Yield: 3.2 g; 1H NMR (400 MHz, CDCl₃): δ 2.59(s, 3H), 7.71 (s, 1H).

1-(5-methylthiazol-2-yl)cyclopropanamine

5-Methylithizole-2-carbonitrile (1.0 g, 1 mmol) was dissolved in THF.Ti(Oi-Pr)₄ (1.2 mmol) was added dropwise to the mixture over a period of5-10 min and the reaction mixture was stirred at rt for 15 min. It wasthen cooled down to 0° C. and EtMgBr (2.5 mmol) was added dropwise overa period of 10-15 min. The reaction mixture was stirred again at 0° C.for 15 min. and then stirred at ambient temperature for 1 h. BF₃.OEt₂(2.5 mmol) was then added dropwise over a period of 5-10 min to themixture that was cooled again to 0° C. After the mixture was stirred for10 min at 0° C. and 1 h at ambient temperature, 1 N NaOH was added tothe mixture cooled to 0° C. DCM was added to the reaction mixture andstirred for 5-10 min. This alkaline solution was filtered through celiteand washed with DCM. The organic layer was concentrated and the residuepurified by flash chromatography on silica gel using 10%chloroform/methanol. Yield: 0.6 g; ¹H NMR (400 MHz, CDCl₃): δ 1.20 (m,2H) 1.31 (m, 2H), 2.40 (s, 3H), 7.26 (s, 1H). LCMS: (ES+) m/z observed154.7.

2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methylthiazol-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.07 g, 1eq), EDCI.HCl (0.13 g, 1.5 eq), HOBT (0.094 g, 1.5 eq) and TEA (0.19 ml,3 eq) were dissolved in dichloromethane and the above solution wasstirred at room temperature for 18 h. Then water was added to themixture and the organic layer was separated. The organic layer waswashed with water and the product was purified by Prep. HPLC. Yield: 65mg (25%) ¹HNMR (400 MHz, CDCl₃): δ 1.43-1.46 (m, 2H), 1.74-1.77 (m, 2H),2.32 (s, 3H), 2.37 (s, 3H), 3.01-3.03 (d, J=5.2 Hz, 3H), 4.04 (s, 3H),5.89 (m, 1H), 6.91 (s, 1H), 7.16 (t, 2H), 7.27 (m, 2H), 7.51 (d, J=4 Hz,1H), 7.66 (s, 1H), 8.00 (m, 2H), 8.13 (s, 1H), 8.7 (s, 1H). LCMS: (ES+)m/z=570.2 (M+H).

General Procedure.

5-(5-(1-cyanocyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide(448 mg) was dissolved in butan-1-ol (22.50 mL) and distributed evenlyinto 15 pre-weighed hydrazides in microwave vials (2-5 mL size) andfollowed by adding K₂CO₃ (8.85 mg) as a solid. The vial was flashed withargon and capped, then heated at 165° C. for 30 minutes in a Biotagemicrowave reactor. The samples were dried by SpeedVac, dissolved in DMF(1.8 mL) and purified by preparative HPLC. Purification method: Cw313a(19×100 mm): Solvent A=5:95 MeCN:Water; Solvent B=95:5 MeCN:Water;Modifier=10 mM NH₄OAc; 0′ (25 mL/min)=30% B, 0.5° (12.5 mL/min)=30% B,2′ (12.5 mL/min)=30% B, 2.5′=30% B, 22′=95% B, 36′=95% B. HPLC puritywas determined using a Waters ZQ with ESCi mass spectrometer. SolventA=5:95 MeCN:Water; Solvent B=95:5 MeCN:Water; Modifier=10 mM NH₄OAc.Retention time was recorded in minutes.

Analytical Method A Waters Xbridge 4.6×50 mm 5 um C18v

Time B % Flow (mL/min) 0.00′ 5 2.00 8.00′ 95 2.00 9.00′ 95 2.00 9.01′ 52.00 10.00 5 2.00

HPLC % Obs. HPLC Structure Rt Purity MS Ion Method

4.73 89.3 587.33 A

4.76 90.6 587.33 A

5.44 88.5 620.37 A

5.4 93.4 616.33 A

5.37 100 620.187 A

3.85 98.3 553.181 A

5 100 616.218 A

5.84 88.8 620.29 A

4.86 100 616.166 A

4.28 100 552.208 A

4.32 100 552.207 A

4.37 95 587.153 A

4.94 94.9 578.118 A

Methyl3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate

LC/MS were performed by using Shimadzu-VP instrument with UV detectionat 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90%H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final %B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=454.08, HPLCR_(t)=1.838 min.

3-Fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid

¹H NMR (500 MHz, CD₃OD) δ 7.96 (m, 2H), 7.76 (s, 1H), 7.75-7.73 (d, 1H),7.56 (d, J=8.24, 1H), 7.33-7.28 (t overlapping with m, 3H), 2.96 (s,3H), 2.20 (s, 3H). LC/MS were performed by using Shimadzu-VP instrumentwith UV detection at 220 nm and Waters Micromass. HPLC method: SolventA=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z(M+H)⁺=440.09, HPLC R_(t)=1.720.

4-Fluoro-5-(3-fluoro-2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.27-7.77 mM. (UVdetection at 220 nm). The material obtained was further purified bypreparative TLC (500 um×20×20 cm plate, 5% MeOH/CH₂Cl₂). Analytical TLCRf=0.30 (5% MeOH/CH₂Cl₂). ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (s, 1H), 8.73(m, 2H), 8.68 (d, J=4.58, 2H), 7.95 (dd, J=8.55, 5.49, 1H), 7.78 (d,J=10.38, 1H), 7.74 (s, 1H), 7.69 (d, J=8.54, 1H), 7.43 (t, J=9.00, 2H),7.39 (d, 1H), 7.28 (t, J=4.88, 1H), 2.81 (d, J=4.58, 3H), 2.14 (s, 3H),1.61 (m, 2H), 1.35 (m, 2H). ¹⁹F NMR (470.45 MHz, DMSO-d₆) δ −110.73,−115.40, −121.76 (The ¹⁹F chemical shift was referenced to CFCl₃ at 0.0ppm). LC/MS were performed by using Shimadzu-VP instrument with UVdetection at 220 nm and Waters Micromass. HPLC method: Solvent A=10%MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0,Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min,Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=557.12, HPLCR_(t)=1.662 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=6.31 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=5.29 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=10.25 min.

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methylpyrazin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

This example was prepared from the coupling of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid with 1-(5-methylpyrazin-2-yl)cyclopropanamine (obtained from5-methylpyrazine-2-carbonitrile by the reaction usingTi(OiPr)₄/EtMgBr/BF₃OEt₂), and was isolated as a TFA salt afterpurification by Shimadzu-VP preparative reverse phase HPLC using theseparation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90%MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10min, Stop time=12 min, Flow Rate=25 mL/min, Column: Sunfire Prep C1819×100 5 um, Fraction Collection: 7.15-7.72 min. (UV detection at 220nm). ¹H NMR (500 MHz, CD₃OD) δ 8.44 (s, 1H), 8.43 (s, 1H), 7.95 (m, 2H),7.90 (dd, J=7.93, 1.83, 1H), 7.83 (s, 1H), 7.55 (d, J=8.55, 1H), 7.49(d, J=7.93, 1H), 7.33 (d, J=8.24, 1H), 7.29 (t, J=8.85, 2H), 2.96 (s,3H), 2.51 (s, 3H), 2.30 (s, 3H), 1.67 (m, 2H), 1.41 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=553.22, HPLCR_(t)=1.647 min. Analytical HPLC were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and 254 nm. Analytical HPLCmethod: Solvent A=5% MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5%H₂O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stoptime=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150mm, R_(t)=6.01 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=5.04 min. Analytical HPLC method: Solvent A=5% MeOH-95% H₂O-10 mMNH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃, Start % B=50, Final %B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min,Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=10.24 min.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(6-methylpyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=20, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Sunfire Prep C18 19×100 5 um, Fraction Collection: 8.12-8.62 min. (UVdetection at 220 nm). The material obtained was further purified bypreparative TLC (500 um×20×20 cm plate, 5% MeOH/CH₂Cl₂). Analytical TLCRf=0.44 (5% MeOH/CH₂Cl₂). ¹H NMR (500 MHz, CD₃OD) δ 7.98 (m, 2H), 7.79(s, 1H), 7.63 (d, J=8.54, 1H), 7.59 (d, J=1.22, 1H), 7.56 (t, J=7.78,1H), 7.34 (dd, J=8.50, 1.83, 1H), 7.32 (d, J=5.19, 1H), 7.28 (apparentt, 2H), 7.14 (s, 1H), 7.01 (d, J=7.63, 1H), 4.08 (s, 3H), 2.96 (s, 3H),2.47 (s, 3H), 2.37 (s, 3H), 1.67 (m, 2H), 1.33 (m, 2H). LC/MS wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=0, Final % B=100,Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column:Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)⁺=564.27, HPLC Rt=1.518min. Analytical HPLC were performed by using Shimadzu-VP instrument withUV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5%MeCN-95% H₂O-0.1% TFA, Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50,Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=2.83 min; Column:Xbridge Phenyl 3.5 um, 4.6×150 mm, R_(t)=3.65 min. Analytical HPLCmethod: Solvent A=5% MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5%H₂O-10 mM NH₄HCO₃, Start % B=50, Final % B=100, Gradient time=15 min,Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um,4.6×150 mm, R_(t)=13.04 min.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-m-tolylcyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Sunfire Prep C18 19×100 5 um, Fraction Collection: 9.77-10.40 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, CD₃OD) δ 7.96 (m, 2H), 7.76 (s,1H), 7.61 (d, J=8.54, 1H), 7.58 (d, J=1.83, 1H), 7.31 (dd, J=8.24, 1.83,1H), 7.26 (apparent t, 2H), 7.17 (t, J=7.63, 1H), 7.12 (d overlappedwith s, 1H), 7.11 (s, 1H), 7.07 (d, J=7.32, 1H), 6.99 (d, J=7.32, 1H),4.06 (s, 3H), 2.94 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 1.35 (broad m,2H), 1.34 (broad m, 2H). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+H)⁺=563.27, HPLC R_(t)=1.962 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=12.30 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=9.32 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=12.78 min.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(3-methyl-1,2,4-oxadiazol-5-ylcarbamoyl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

Purification was performed by Shimadzu-VP preparative reverse phase HPLCusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column:Sunfire Prep C18 19×100 5 um, Fraction Collection: 7.07-7.87 min. (UVdetection at 220 nm). ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.48 (q,J=4.78, 1H), 7.99 (m, 2H), 7.74 (s, 1H), 7.73 (d overlapped with s, 1H),7.50 (d, J=1.53, 1H), 7.41 (t, J=9.00, 2H), 7.33 (dd, J=8.39, 1.68, 1H),7.17 (s, 1H), 4.00 (s, 3H), 2.82 (d, J=4.78, 3H), 2.31 (s, 3H), 2.25 (s,3H), 1.55 (m, 2H), 1.23 (m, 2H). LC/MS were performed by usingShimadzu-VP instrument with UV detection at 220 nm and Waters Micromass.HPLC method: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10;(ES+) m/z (M+Na)⁺=620.22, HPLC Rt=1.668 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 220 nmand 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=50, Final % B=100,Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column:Sunfire C18, 3.5 um, 4.6×150 mm, R_(t)=6.33 min; Column: Xbridge Phenyl3.5 um, 4.6×150 mm, R_(t)=5.18 min. Analytical HPLC method: Solvent A=5%MeOH-95% H₂O-10 mM NH₄HCO₃, Solvent B=95% MeOH-5% H₂O-10 mM NH₄HCO₃,Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min,Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm,R_(t)=8.65 min.

The following examples were synthesized in a similar fashion to thatdescribed for2-(4-fluorophenyl)-5-(4-isopropoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamideusing the same conditions for preparative HPLC, analytical HPLC andLCMS.

5-(4-Ethoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.28-1.35 (m, 2H), 1.53 (t, J=6.86 Hz,3H), 1.63-1.70 (m, 2H), 2.29 (s, 3 H), 2.88 (d, J=4.52 Hz, 3H), 4.29 (q,J=6.86 Hz, 2H), 7.04 (s, 1H), 7.14-7.28 (m, 4H), 7.53-7.63 (m, 4H),7.68-7.75 (m, 1H), 7.91 (s, 1H), 8.11-8.18 (m, 2H), 8.51 (d, J=4.02 Hz,1H), 8.72 (s, 1H). LCMS m/z 564.6 (M+H), rt=2.676 min. HPLC (SunfireC18) rt=7.536 min, 99.6% purity and (XBridge Phenyl C18) rt=11.754 min.,96.9% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-4-propoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.10 (t, J=7.40 Hz, 3H), 1.27-1.34 (m,2H), 1.64-1.70 (m, 2H), 1.90-2.00 (m, 2H), 2.29 (s, 3H), 2.88 (d, J=4.52Hz, 3H), 4.20 (t, J=6.53 Hz, 2H), 7.05 (s, 1H), 7.12-7.17 (m, 1H),7.17-7.29 (m, 3H), 7.52-7.60 (m, 3H), 7.61 (d, J=1.25 Hz, 1H), 7.65-7.72(m, 1H), 7.93 (s, 1H), 8.10-8.19 (m, 2H), 8.49 (d, J=4.77 Hz, 1H), 8.69(s, 1H). LCMS m/z 578.6 (M+h), rt=2.838 min. HPLC (Sunfire C18) rt=8.074min, 99.8% purity and (XBridge Phenyl C18) rt=12.011 min., 99.4% purity.

2-(4-Fluorophenyl)-5-(4-isobutoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.10 (d, J=6.78 Hz, 6H), 1.24-1.33 (m,2H), 1.64-1.71 (m, 2H), 2.17-2.27 (m, 1H), 2.29 (s, 3H), 2.88 (d, J=4.77Hz, 3H), 4.03 (d, J=6.27 Hz, 2H), 7.03-7.12 (m, 2H), 7.18-7.31 (m, 3H),7.50 (d, J=8.03 Hz, 1H), 7.54-7.66 (m, 4H), 7.95 (s, 1H), 8.10-8.22 (m,2H), 8.43 (d, J=4.02 Hz, 1H), 8.63 (s, 1H). LCMS m/z 592.6 (M+H),rt=2.991 min. HPLC (Sunfire C18) rt=8.511 min, 100% purity and (XBridgePhenyl C18) rt=12.194 min., 99.4% purity.

5-(4-Butoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.00 (t, J=7.40 Hz, 3H), 1.27-1.37 (m,2H), 1.56 (m, 2H), 1.64-1.71 (m, 2 H), 1.86-1.99 (m, 2H), 2.29 (s, 3H),2.88 (d, J=4.77 Hz, 3H), 4.24 (t, J=6.53 Hz, 2 H), 7.05 (s, 1H),7.14-7.30 (m, 4H), 7.51-7.64 (m, 4H), 7.71 (td, J=7.78, 1.76 Hz, 1H),7.92 (s, 1H), 8.08-8.18 (m, 2H), 8.51 (d, J=5.02 Hz, 1H), 8.71 (s, 1H).LCMS m/z 592.5 (M+H), rt=2.940 min. HPLC (Sunfire C18) rt=8.291 min,100% purity and (XBridge Phenyl C18) rt=12.116 min., 100% purity.

2-(4-Fluorophenyl)-5-(4-(isopentyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.00 (d, J=6.53 Hz, 6H), 1.24-1.32 (m,2H), 1.64-1.70 (m, 2H), 1.79-1.92 (m, 3H), 2.29 (s, 3H), 2.88 (d, J=4.77Hz, 3H), 4.27 (t, J=6.53 Hz, 2H), 7.06-7.12 (m, 2H), 7.18-7.29 (m, 3H),7.48-7.59 (m, 3H), 7.59-7.65 (m, 2H), 7.94 (s, 1H), 8.11-8.18 (m, 2H),8.42-8.47 (m, 1H), 8.62 (s, 1H). LCMS m/z 606.6 (M+H), rt=3.085 min.HPLC (Sunfire C18) rt=8.664 min, 100% purity and (XBridge Phenyl C18)rt=12.283 min., 100% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-4-(prop-2-ynyloxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.28 (q, J=4.02 Hz, 2H), 1.62-1.69 (m,2H), 2.30 (s, 3H), 2.89 (d, J=4.52 Hz, 3H), 3.19 (t, J=2.38 Hz, 1H),5.00 (d, J=2.51 Hz, 2H), 7.00 (ddd, J=7.15, 4.77, 1.38 Hz, 1H), 7.15 (s,1H), 7.18-7.31 (m, 3H), 7.46-7.59 (m, 4H), 7.63 (d, J=1.00 Hz, 1H), 7.94(s, 1H), 8.11-8.20 (m, 2H), 8.35-8.41 (m, 1 H), 8.46 (s, 1H). LCMS m/z574.5 (M+H), rt=2.625 min. HPLC (Sunfire C18) rt=7.381 min, 100% purityand (XBridge Phenyl C18) rt=11.309 min., 98.4% purity.

5-(4-(2-(Dimethylamino)ethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.34-1.38 (m, 2H), 1.60-1.66 (m, 2H),2.28 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 2.91 (s, 6H), 3.64 (t, J=5.02 Hz,2 H), 4.64 (t, J=5.02 Hz, 2H), 7.16 (s, 1H), 7.19-7.29 (m, 4H),7.51-7.58 (m, 2H), 7.61-7.69 (m, 3H), 7.89 (br. s., 1H), 8.07-8.14 (m,2H), 8.51 (d, J=5.02 Hz, 1H), 8.85 (s, 1H). LCMS m/z 607.5 (M+H),rt=1.952 min. HPLC (Sunfire C18) rt=5.690 min, 100% purity and (XBridgePhenyl C18) rt=11.743 min., 99.6% purity.

5-(4-(3-(Dimethylamino)propoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.31-1.37 (m, 2H), 1.62-1.69 (m, 2H),2.29 (s, 3H), 2.35 (t, J=6.02 Hz, 2H), 2.76 (s, 6H), 2.88 (d, J=4.52 Hz,3H), 3.35 (t, J=6.53 Hz, 2H), 4.33 (t, J=5.77 Hz, 2H), 7.08 (s, 1H),7.18-7.30 (m, 4 H), 7.52-7.65 (m, 4H), 7.67 (s, 1H), 7.80 (td, J=7.72,1.63 Hz, 1H), 8.07-8.15 (m, 2H), 8.51 (d, J=5.02 Hz, 1H), 8.92 (s, 1H).LCMS m/z 621.6 (M+H), rt=2.048 min. HPLC (Sunfire C18) rt=5.911 min,100% purity and (XBridge Phenyl C18) rt=11.653 min., 100% purity.

5-(4-Cyclobutoxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.27-1.36 (m, 2H), 1.62-1.69 (m, 2H),1.75-1.81 (m, 1H), 1.92 (d, J=10.04 Hz, 1H), 2.23-2.36 (m, 5H),2.51-2.64 (m, 2H), 2.88 (d, J=4.77 Hz, 3 H), 4.92 (t, J=7.28 Hz, 1H),6.87 (s, 1H), 7.13 (ddd, J=7.47, 4.96, 1.13 Hz, 1H), 7.17-7.28 (m, 3H),7.51-7.63 (m, 4H), 7.64-7.72 (m, 1H), 7.91 (s, 1H), 8.10-8.20 (m, 2H),8.48 (d, J=5.02 Hz, 1H), 8.64 (s, 1H). LCMS m/z 590.5 (M+H), rt=2.823min. HPLC (Sunfire C18) rt=7.996 min, 91.3% purity and (XBridge PhenylC18) rt=12.013 min., 91.7% purity.

5-(4-(Cyclohexyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.26-1.34 (m, 2H), 1.33-1.55 (m, 3H),1.56-1.64 (m, 1H), 1.65-1.70 (m, 4H), 1.76-1.87 (m, 2H), 2.06-2.18 (m,2H), 2.28 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 4.65 (t, J=3.89 Hz, 1H),7.05-7.13 (m, 2H), 7.17-7.31 (m, 3H), 7.50-7.59 (m, 3H), 7.59-7.68 (m,2H), 7.96 (s, 1H), 8.10-8.20 (m, 2H), 8.46 (d, J=4.02 Hz, 1H), 8.74 (s,1H). LCMS m/z 618.6 (M+H), rt=3.070 min. HPLC (Sunfire C18) rt=8.723min, 100% purity and (XBridge Phenyl C18) rt=12.421 min., 99.8% purity.

2-(4-Fluorophenyl)-5-(4-(3-methoxypropoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.24-1.32 (m, 2H), 1.64-1.69 (m, 2H),2.10-2.20 (m, 2H), 2.29 (s, 3H), 2.89 (d, J=4.77 Hz, 3H), 3.22 (s, 3H),3.53-3.58 (m, 2 H), 4.31 (t, J=5.90 Hz, 2H), 7.00 (ddd, J=7.40, 4.77,1.13 Hz, 1H), 7.05 (s, 1H), 7.16-7.30 (m, 3H), 7.43-7.48 (m, 1H),7.50-7.59 (m, 3H), 7.62 (d, J=1.25 Hz, 1H), 7.96 (s, 1H), 8.11-8.21 (m,2H), 8.38 (dd, J=4.77, 1.00 Hz, 1H), 8.69 (s, 1H). LCMS m/z 608.5 (M+H),rt=2.625 min. HPLC (Sunfire C18) rt=7.536 min, 100% purity and (XBridgePhenyl C18) rt=11.788 min., 99.2% purity.

5-(4-(2-Cyclopropylethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.13-0.20 (m, 2H), 0.45-0.54 (m, 2H),0.89 (s, 1H), 1.28-1.34 (m, 2H), 1.63-1.70 (m, 2H), 1.83 (q, J=6.69 Hz,2H), 2.29 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 4.30 (t, J=6.65 Hz, 2H),7.08 (s, 1H), 7.13-7.30 (m, 4H), 7.53-7.64 (m, 4H), 7.70 (td, J=7.78,1.76 Hz, 1H), 7.93 (s, 1 H), 8.10-8.19 (m, 2H), 8.50 (d, J=5.02 Hz, 1H),8.73 (s, 1H). LCMS m/z 604.5 (M+H), rt=2.948 min. HPLC (Sunfire C18)rt=8.483 min, 100% purity and (XBridge Phenyl C18) rt=12.218 min., 100%purity.

5-(4-(Benzyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.07-1.16 (m, 2H), 1.52-1.60 (m, 2H),2.30 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 5.32 (s, 2H), 7.08 (ddd, J=7.40,4.89, 1.25 Hz, 1H), 7.16-7.29 (m, 4H), 7.31-7.42 (m, 3H), 7.46 (d,J=8.03 Hz, 1H), 7.51-7.60 (m, 5H), 7.63 (d, J=1.25 Hz, 1H), 7.93 (s,1H), 8.10-8.18 (m, 2H), 8.43 (d, J=5.02 Hz, 1H), 8.59 (s, 1H). LCMS m/z626.5 (M+H), rt=2.896 min. HPLC (Sunfire C18) rt=8.369 min, 100% purityand (XBridge Phenyl C18) rt=12.173 min., 100% purity.

5-(4-(2-Chlorobenzyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.05-1.18 (m, 2H), 1.51-1.61 (m, 2H),2.31 (s, 3H), 2.89 (d, J=4.77 Hz, 3H), 5.34-5.52 (m, 2H), 7.01-7.08 (m,1H), 7.17-7.25 (m, 3H), 7.28 (dd, J=8.53, 1.76 Hz, 1H), 7.32-7.38 (m,2H), 7.41-7.60 (m, 5H), 7.64 (d, J=1.25 Hz, 1H), 7.66-7.71 (m, 1H), 7.91(s, 1H), 8.11-8.19 (m, 2H), 8.40 (d, J=4.02 Hz, 1H), 8.48 (s, 1H). LCMSm/z 660.5 (M), 663.4 (M+3H), rt=3.028 min. HPLC (Sunfire C18) rt=8.764min, 100% purity and (XBridge Phenyl C18) rt=12.324 min., 99.7% purity.

5-(4-(3-Chlorobenzyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.17-1.24 (m, 2H), 1.57-1.63 (m, 2H),2.29 (s, 3H), 2.88 (d, J=4.52 Hz, 3H), 5.33 (s, 2H), 7.12-7.17 (m, 2H),7.18-7.29 (m, 3H), 7.33-7.42 (m, 2H), 7.46-7.59 (m, 4H), 7.60-7.69 (m,3H), 7.89 (s, 1H), 8.09-8.18 (m, 2H), 8.45-8.51 (m, 1H), 8.64 (s, 1H).LCMS m/z 660.5 (M), 663.5 (M+3H), rt=3.023 min. HPLC (Sunfire C18)rt=8.546 min, 97.9% purity and (XBridge Phenyl C18) rt=12.308 min.,97.4% purity.

5-(4-(4-Chlorobenzyloxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.15-1.21 (m, 2H), 1.55-1.63 (m, 2H),2.28 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 5.32 (s, 2H), 7.14 (s, 1H),7.15-7.28 (m, 4H), 7.38-7.44 (m, 2H), 7.51-7.60 (m, 5H), 7.62 (d, J=1.25Hz, 1H), 7.67 (td, J=7.78, 1.76 Hz, 1H), 7.88 (s, 1H), 8.09-8.18 (m,2H), 8.50 (d, J=4.27 Hz, 1H), 8.65 (s, 1H). LCMS m/z 660.5 (M), 663.5(M+3H), rt=3.046 min. HPLC (Sunfire C18) rt=8.679 min, 97.9% purity and(XBridge Phenyl C18) rt=12.268 min., 97.5% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-4-phenethoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.12-1.18 (m, 2H), 1.59-1.65 (m, 2H),2.29 (s, 3H), 2.87 (d, J=4.77 Hz, 3H), 3.23 (t, J=6.53 Hz, 2H), 4.51 (t,J=6.53 Hz, 2H), 7.05-7.14 (m, 3H), 7.16-7.26 (m, 5H), 7.29 (d, J=7.03Hz, 2H), 7.39 (d, J=8.03 Hz, 1H), 7.52-7.64 (m, 4H), 7.94 (s, 1H),8.11-8.18 (m, 2H), 8.39 (s, 1H), 8.43-8.47 (m, 1H). LCMS m/z 640.6(M+H), rt=2.996 min. HPLC (Sunfire C18) rt=8.448 min, 99.7% purity and(XBridge Phenyl C18) rt=12.341 min., 98.2% purity.

2-(4-Fluorophenyl)-5-(4-(4-methoxyphenethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.14-1.23 (m, 2H), 1.61-1.67 (m, 2H),2.28 (s, 3H), 2.87 (d, J=4.77 Hz, 3H), 3.16 (t, J=6.53 Hz, 2H), 3.58 (s,3H), 4.47 (t, J=6.53 Hz, 2H), 6.70-6.77 (m, 2H), 7.09 (s, 1H), 7.13 (dd,J=7.03, 5.52 Hz, 1H), 7.16-7.26 (m, 5H), 7.39 (d, J=8.03 Hz, 1H),7.51-7.68 (m, 4H), 7.94 (s, 1H), 8.08-8.19 (m, 2H), 8.42 (s, 1H), 8.49(d, 1H). LCMS m/z 670.6 (M+H), rt=2.965 min. HPLC (Sunfire C18) rt=8.329min, 100% purity and (XBridge Phenyl C18) rt=12.301 min., 98.7% purity.

5-(4-(4-(Dimethylamino)phenethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.08-1.18 (m, 2H), 1.58-1.65 (m, 2H),2.29 (s, 3H), 2.78 (s, 6H), 2.88 (d, J=4.52 Hz, 3H), 3.10 (t, J=6.27 Hz,2 H), 4.45 (t, J=6.40 Hz, 2H), 6.55 (d, J=8.78 Hz, 2H), 7.00 (ddd,J=7.53, 4.77, 1.00 Hz, 1H), 7.07-7.14 (m, 3H), 7.17-7.34 (m, 4H), 7.49(td, J=7.72, 1.88 Hz, 1H), 7.53-7.57 (m, 2H), 7.61 (d, J=1.26 Hz, 1H),7.97 (s, 1H), 8.11-8.20 (m, 2H), 8.31 (s, 1H), 8.36-8.41 (m, 1H). LCMSm/z 683.6 (M+H), rt=2.303 min. HPLC (Sunfire C18) rt=6.475 min, 100%purity and (XBridge Phenyl C18) rt=12.563 min., 97.9% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.39-1.48 (m, 2H), 1.62-1.69 (m, 2H),2.28 (s, 3H), 2.69 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 3.35-3.45 (m, 4H),3.45-3.56 (m, 6 H), 4.53 (t, J=4.77 Hz, 2H), 7.10 (s, 1H), 7.18-7.29 (m,3H), 7.33-7.44 (m, 1H), 7.52-7.66 (m, 3H), 7.69-7.78 (m, 2H), 7.92-8.02(m, 1H), 8.06-8.17 (m, 2H), 8.61 (d, J=5.27 Hz, 1H), 9.10 (s, 1H). LCMSm/z 662.6 (M+H), rt=1.983 min. HPLC (Sunfire C18) rt=5.590 min, 99.5%purity and (XBridge Phenyl C18) rt=11.491 min., 99.1% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.25-1.35 (m, 2H), 1.63-1.70 (m, 2H),1.76-1.90 (m, 2H), 2.09-2.20 (m, 2H), 2.28 (s, 3H), 2.88 (d, J=4.77 Hz,3H), 3.49-3.57 (m, 2H), 3.93 (ddd, J=11.80, 4.52, 4.27 Hz, 2H), 4.84(ddd, J=8.47, 4.52, 4.33 Hz, 1H), 7.01 (ddd, 1H), 7.12 (s, 1H),7.18-7.29 (m, 3H), 7.42-7.48 (m, 1H), 7.51-7.59 (m, 3H), 7.62 (d, J=1.25Hz, 1H), 7.94 (s, 1H), 8.09-8.18 (m, 2H), 8.37-8.43 (m, 1H), 8.59 (s,1H). LCMS m/z 620.6 (M+H), rt=2.570 min. HPLC (Sunfire C18) rt=7.425min, 99.3% purity and (XBridge Phenyl C18) rt=11.581 min., 99.4% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-(pyridin-2-ylmethoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.24-1.32 (m, 2H), 1.64-1.71 (m, 2H),2.30 (s, 3H), 2.89 (d, J=4.77 Hz, 3H), 5.45 (s, 2H), 6.93-7.02 (m, 1H),7.15-7.31 (m, 5H), 7.41-7.52 (m, 3H), 7.57 (d, J=8.53 Hz, 2H), 7.64 (d,J=1.25 Hz, 1H), 7.76 (td, J=7.65, 1.76 Hz, 1H), 7.99 (s, 1H), 8.12-8.21(m, 2H), 8.33-8.41 (m, 1H), 8.55 (d, J=4.02 Hz, 1H), 9.58 (s, 1H). LCMSm/z 627.5 (M+H), rt=2.368 min. HPLC (Sunfire C18) rt=6.703 min, 99.7%purity and (XBridge Phenyl C18) rt=11.521 min., 99.7% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-((tetrahydrofuran-3-yl)methoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.23-1.33 (m, 2H), 1.63-1.69 (m, 2H),1.76-1.85 (m, 1H), 2.07-2.17 (m, 1H), 2.29 (s, 3H), 2.78-2.86 (m, 1H),2.88 (d, J=4.52 Hz, 3H), 3.60-3.66 (m, 1 H), 3.73-3.88 (m, 3H),4.16-4.24 (m, 2H), 7.00 (ddd, J=7.40, 4.77, 1.13 Hz, 1H), 7.07 (s, 1H),7.17-7.30 (m, 3H), 7.45 (d, J=7.78 Hz, 1H), 7.51-7.66 (m, 4H), 7.95 (s,1H), 8.10-8.19 (m, 2H), 8.39 (d, J=4.02 Hz, 1H), 8.55 (s, 1H). LCMS m/z620.6 (M+H), rt=2.850 min. HPLC (Sunfire C18) rt=7.376 min, 99.1% purityand (XBridge Phenyl C18) rt=11.673 min., 98.7% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF) ppm 1.27 (m, 2H), 1.48 (m, 4H), 1.67 (m, 2H), 1.80(m, 2H), 2.28 (s, 3H), 2.89 (d, J=5 Hz, 3H), 3.40 (d, J=3 Hz, 1H), 3.77(m, 1H), 3.90 (d, J=11 Hz, 1H), 4.06 (dd, J=10, 7 Hz, 1H), 4.31 (dd,J=10, 3 Hz, 1H), 7.01 (ddd, 1H), 7.05 (s, 1H), 7.23 (m, 3H), 7.53 (m,4H), 7.62 (d, J=1 Hz, 1H), 7.97 (s, 1H), 8.16 (m, 2H), 8.40 (m, 1 H),9.02 (s, 1H). LCMS m/z 634.6 (M+H), rt=2.876 min. HPLC (Sunfire C18)rt=7.981 min, 100% purity and (XBridge Phenyl C18) rt=12.164 min., 100%purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-4-(pyrazin-2-ylmethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.24-1.32 (m, 2H), 1.64-1.70 (m, 2H),2.31 (s, 3H), 2.89 (d, J=4.77 Hz, 3H), 5.52 (s, 2H), 6.97 (ddd, J=6.84,4.96, 1.51 Hz, 1H), 7.17-7.25 (m, 3H), 7.28 (dd, J=8.53, 1.76 Hz, 1H),7.40-7.49 (m, 2H), 7.52-7.61 (m, 2H), 7.64 (d, J=1.25 Hz, 1H), 7.98 (s,1H), 8.10-8.21 (m, 2H), 8.33-8.41 (m, 1H), 8.52-8.60 (m, 2H), 8.81 (d,J=1.26 Hz, 1H), 9.22 (s, 1H). LCMS m/z 628.6 (M+H), rt=2.462 min. HPLC(Sunfire C18) rt=7.028 min, 100% purity and (XBridge Phenyl C18)rt=11.429 min., 100% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-(pyridin-3-ylmethoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.26-1.36 (m, 2H), 1.54-1.62 (m, 2H),2.26 (s, 3H), 2.87 (d, J=4.77 Hz, 3H), 5.51 (s, 2H), 7.13 (s, 1H),7.17-7.29 (m, 3H), 7.41-7.48 (m, 1H), 7.55 (d, J=8.03 Hz, 1H), 7.58-7.65(m, 2H), 7.75-7.85 (m, 3H), 7.99 (td, J=7.78, 1.76 Hz, 1H), 8.06-8.14(m, 2H), 8.50 (d, J=8.03 Hz, 1H), 8.62 (d, J=4.52 Hz, 1H), 8.77-8.84 (m,1H), 8.96-9.07 (m, 2H). LCMS m/z 627.5 (M+H), rt=2.062 min. HPLC(Sunfire C18) rt=5.808 min, 100% purity and (XBridge Phenyl C18)rt=11.143 min., 99.5% purity.

5-(4-(2-(1H-Imidazol-1-yl)ethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.24-1.32 (m, 2H), 1.59-1.65 (m, 2H),2.27 (s, 3H), 2.88 (d, J=4.52 Hz, 3H), 4.61 (t, J=4.64 Hz, 2H), 4.78 (t,J=4.52 Hz, 2H), 7.03 (s, 1H), 7.17-7.29 (m, 4H), 7.44 (s, 1H), 7.48-7.69(m, 5 H), 7.71-7.81 (m, 2H), 8.06-8.15 (m, 2H), 8.49 (d, J=4.02 Hz, 1H),8.59 (s, 1H), 9.02 (s, 1H). LCMS m/z 630.5 (M+H), rt=2.015 min. HPLC(Sunfire C18) rt=5.895 min, 100% purity and (XBridge Phenyl C18)rt=11.013 min., 100% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-(pyridin-4-ylmethoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.34-1.43 (m, 2H), 1.58-1.65 (m, 2H),2.23 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 5.60 (s, 2H), 7.02 (s, 1H),7.17-7.28 (m, 3H), 7.48 (td, J=6.53, 1.00 Hz, 1H), 7.55 (d, J=8.03 Hz,1H), 7.58-7.65 (m, 2H), 7.77 (s, 1H), 7.85 (d, J=8.03 Hz, 1H), 7.96-8.06(m, 3H), 8.06-8.15 (m, 2H), 8.63 (d, J=4.52 Hz, 1H), 8.85 (d, J=6.53 Hz,2H), 9.14 (s, 1H). LCMS m/z 627.5 (M+H), rt=2.030 min. HPLC (SunfireC18) rt=5.740 min, 100% purity and (XBridge Phenyl C18) rt=11.278 min.,100% purity.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-4-(2-morpholinoethoxy)-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.43-1.55 (m, 2H), 1.65-1.72 (m, 2H),2.27 (s, 3H), 2.88 (d, J=4.77 Hz, 3H), 3.37 (br. s., 4H), 3.68 (t,J=4.89 Hz, 2H), 3.81 (br. s., 4H), 4.66 (t, J=4.77 Hz, 2H), 7.12-7.32(m, 4H), 7.50 (td, J=6.53, 1.00 Hz, 1H), 7.56 (d, J=8.53 Hz, 1H), 7.62(d, J=1.25 Hz, 1H), 7.63-7.70 (m, 2H), 7.78 (d, J=8.03 Hz, 1H),8.02-8.16 (m, 3H), 8.60-8.70 (m, 1H), 9.26 (s, 1H). LCMS m/z 649.5(M+H), rt=2.112 min. HPLC (Sunfire C18) rt=9.464 min, 100% purity and(XBridge Phenyl C18) rt=15.487 min., 99.9% purity.

An alternative approach to the synthesis of 4′ ether linked analogs isthe treatment of the 4′-phenol-benzofuran with alkyl bromides and anexcess of cesium carbonate in DMF. This route is shown below.

5-(4-(2-Amino-2-oxoethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a sealed tube was added DMF (2 mL),2-(4-fluorophenyl)-5-(4-hydroxy-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide(40.2 mg, 0.075 mmol), 2-bromoacetamide (31.0 mg, 0.225 mmol) and cesiumcarbonate (98 mg, 0.300 mmol). The tube was sealed and the mixtureheated overnight at 85° C. The reaction mixture was cooled to roomtemperature, diluted with methanol (2 mL) and the crude product waspurified using a Shimadzu preparative HPLC employingmethanol/water/trifluoroacetic acid where solvent A was 10% methanol/90%water/0.1% trifluoroacetic acid and solvent B was 10% water/90%methanol/0.1% trifluoroacetic acid with a Phenomenex-Luna 10 μm C1830×100 mm column at a gradient of 30-100% B and a flow rate of 40mL/min. over 12 minutes with a 10 minute hold. The LC/MS data wasobtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220nm using the following set of conditions: The LC/MS data was obtained ona Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm usingthe following set of conditions: Phenomenex Luna 3 μm C18, 2×50 mmcolumn, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1%trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1%trifluoroacetic acid/10% HPLC grade acetonitrile), in 4 minutes with a 1minute hold at a rate of 0.8 mL/minute. HPLC purity was determined usinga Shimadzu analytical LC at 254 nm and 256 nm with a Waters Sunfire C183.5 μm 4.6×150 mm column employing water/acetonitrile/0.1% TFA with agradient of 10-100% B (B=95% HPLC grade acetonitrile/0.1%trifluoroacetic acid/5% HPLC grade water), (A=95% HPLC grade water/0.1%trifluoroacetic acid/5% HPLC grade acetonitrile), in 10 minutes with a10 minute hold at a rate of 1 mL/minute. The HPLC purity was thenconfirmed with an orthogonal solvent system and column using a Shimadzuanalytical LC with a Waters XBridge Phenyl C18 3.5 μm 4.6×150 mm columnemploying water/methanol/10 mM ammonium bicarbonate with a gradient of10-100% B (B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLCgrade water), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLCgrade methanol), in 10 minutes with a 10 minute hold at a rate of 1mL/minute. Obtained 34.5 mgs of TFA salt of5-(4-(2-amino-2-oxoethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,as a white solid (77.0% yield). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.75-1.88(m, 4H), 2.35 (s, 3H), 2.93 (s, 3H), 4.87 (s, 2H), 7.08 (s, 1H),7.23-7.35 (m, 3H), 7.56 (d, J=1.25 Hz, 1H), 7.63 (d, J=8.53 Hz, 1H),7.76-7.88 (m, 3H), 7.91-8.00 (m, 2H), 8.43 (td, J=7.97, 1.63 Hz, 1H),8.56-8.63 (m, 1H). LCMS m/z 593.5 (M+H), rt=2.232 min., 100% purity.HPLC (Sunfire C18) rt=6.306 min, 99.5% purity and (XBridge Phenyl C18)rt=9.889 min., 99.1% purity.

The following examples were synthesized in a similar fashion to thatdescribed for5-(4-(2-amino-2-oxoethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide,and using the same conditions for preparative HPLC, analytical HPLC andLCMS.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.27-1.35 (m, 2H), 1.41-1.55 (m, 2H),1.63-1.69 (m, 2H), 1.75-1.80 (m, 2 H), 2.21 (d, 1H), 2.28 (s, 3H), 2.88(d, J=4.77 Hz, 3H), 3.32-3.44 (m, 2H), 3.92 (dd, J=11.29, 3.01 Hz, 2H),4.09 (d, J=6.27 Hz, 2H), 7.05 (s, 1H), 7.13-7.29 (m, 4 H), 7.47-7.64 (m,4H), 7.70 (t, J=7.65 Hz, 1H), 7.89 (s, 1H), 8.08-8.19 (m, 2H), 8.50 (d,J=4.52 Hz, 1H), 8.62 (s, 1H). LCMS m/z 634.5 (M+H), rt=2.650 min. HPLC(Sunfire C18) rt=7.225 min, 100% purity and (XBridge Phenyl C18)rt=12.039 min., 99.5% purity.

5-(4-(Cyanomethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.29-1.35 (m, 2H), 1.62-1.67 (m, 2H),2.33 (s, 3H), 2.89 (d, J=4.77 Hz, 3H), 5.20 (s, 2H), 7.08-7.13 (m, 1H),7.17 (s, 1H), 7.22 (t, J=8.91 Hz, 2H), 7.28 (dd, J=8.53, 1.76 Hz, 1H),7.51-7.57 (m, 1H), 7.58 (d, J=8.28 Hz, 2H), 7.63-7.69 (m, 2H), 7.85 (s,1H), 8.10-8.18 (m, 2H), 8.40-8.49 (m, 2H). LCMS m/z 575.5 (M+H),rt=2.475 min. HPLC (Sunfire C18) rt=7.165 min, 98.8% purity and (XBridgePhenyl C18) rt=11.124 min., 98.7% purity.

5-(4-(Cyclopropylmethoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 0.39-0.49 (m, 2H), 0.62-0.71 (m, 2H),1.27-1.37 (m, 2H), 1.38-1.49 (m, 1H), 1.64-1.70 (m, 2H), 2.28 (s, 3 H),2.88 (d, J=4.77 Hz, 3H), 4.08 (d, J=7.03 Hz, 2H), 7.01 (s, 1H),7.14-7.28 (m, 4H), 7.52-7.65 (m, 4H), 7.71 (dd, J=7.53, 1.51 Hz, 1H),7.91-7.96 (m, 1H), 8.09-8.18 (m, 2H), 8.52 (d, J=4.77 Hz, 1H), 8.90 (s,1H). LCMS m/z 590.6 (M+H), rt=2.841 min. HPLC (Sunfire C18) rt=8.029min, 100% purity and (XBridge Phenyl C18) rt=12.101 min., 100% purity.

5-(4-(3-Amino-3-oxopropoxy)-2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

¹H NMR (400 MHz, THF-d8) δ ppm 1.34-1.41 (m, 2H), 1.61-1.66 (m, 2H),2.29 (s, 3H), 2.73 (t, J=5.65 Hz, 2H), 2.89 (d, J=4.77 Hz, 3H), 4.45 (t,J=5.77 Hz, 2H), 6.56 (br. s., 1H), 7.02 (br. s., 1H), 7.08 (s, 1H), 7.15(m, 1H), 7.17-7.30 (m, 3H), 7.52-7.63 (m, 4H), 7.66-7.74 (m, 1H), 7.91(s, 1H), 8.10-8.20 (m, 2H), 8.47-8.55 (m, 1H), 8.85 (s, 1H). LCMS m/z607.6 (M+H), rt=2.308 min. HPLC (Sunfire C18) rt=6.441 min, 96.7% purityand (XBridge Phenyl C18) rt=10.639 min., 98.8% purity.

Methyl2-(4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-5-methyl-2-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenoxy)acetate

¹H NMR (400 MHz, THF-d8) δ ppm 1.32-1.40 (m, 2H), 1.68 (m, 2H), 2.29 (s,3H), 2.88 (d, J=4.52 Hz, 3H), 3.80 (s, 3H), 4.95 (s, 2H), 7.00-7.10 (m,2H), 7.17-7.31 (m, 3 H), 7.47-7.67 (m, 5H), 7.99-8.05 (m, 1H), 8.10-8.20(m, 2H), 8.45 (d, J=4.02 Hz, 1H), 9.23 (s, 1H). LCMS m/z 608.5 (M+H),rt=2.507 min., 98.6% purity. HPLC (Sunfire C18) rt=7.203 min, 99.1%purity and (XBridge Phenyl C18) rt=11.494 min., 97.1% purity.

5-(2-(2-Amino-2-oxoethoxy)-5-(tert-butylcarbamoyl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 25 mL flask was added4-(2-amino-2-oxoethoxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxybenzoic acid (49.2 mg, 0.1 mmol),DMF (2 mL), N-ethyl-N-diisopropylpropan-2-amine (0.069 mL, 0.396 mmol),2-methylpropan-2-amine (18 mg, 26 μL, 0.246 mmol) and finally HATU(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V), 151 mg, 0.396 mmol). The flask wassealed with a septum, placed under N₂ and stirred at room temperatureovernight. The crude product was purified using a Shimadzu preparativeHPLC employing acetonitrile/water/trifluoroacetic acid where solvent Awas 10% acetonitrile/90% water/0.1% trifluoroacetic acid and solvent Bwas 10% water/90% acetonitrile/0.1% trifluoroacetic acid with a WatersSunfire 5 μm C18 19×150 mm column at a gradient of 20-100% B and a flowrate of 25 mL/min. over 22 minutes with a 8 minute hold. The solvent wasremoved giving 28.3 mgs (52% yield) of5-(2-(2-amino-2-oxoethoxy)-4-methoxy-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a yellow powder. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with aPhenomenex Gemini C18 3.0 μm 4.6×150 mm column employingwater/methanol/10 mM ammonium bicarbonate with a gradient of 10-100% B(B=95% HPLC grade methanol/10 mM ammonium bicarbonate/5% HPLC gradewater), (A=95% HPLC grade water/10 mM ammonium bicarbonate/5% HPLC grademethanol), in 10 minutes with a 10 minute hold at a rate of 1 mL/minute.¹H NMR (400 MHz, THF-d8) δ ppm 1.43 (s, 9H), 2.91 (d, J=4.77 Hz, 3H),4.03 (s, 3H), 4.51 (s, 2H), 6.43 (br. s., 1H), 6.71-6.77 (m, 1H), 6.78(s, 1H), 7.21 (t, J=8.78 Hz, 2H), 7.46-7.52 (m, 1H), 7.52-7.54 (m, 1H),7.54-7.59 (m, 1H), 7.67 (s, 1H), 7.92 (s, 1H), 8.10-8.16 (m, 2H), 8.19(s, 1 H). LCMS rt=2.976 min., m/z 548.2 (M+H), 98.3% purity. HPLCrt=9.088 min. (Sunfire C18), 99.0% purity and 11.588 min. (Gemini C18),99.4% purity.

3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoic acid

To a small sealed tube was added4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yltrifluoromethanesulfonate (64.5 mg, 0.111 mmol), dioxane (6 mL), water(1.200 mL), 3-borono-4-methoxybenzoic acid (26.1 mg, 0.133 mmol), cesiumcarbonate (54.2 mg, 0.167 mmol) and finallyTetrakis(triphenylphosphine)palladium(0) (2.6 mg, 2.2 μmol). The tubewas sealed and the reaction mixture heated at 85° C. for twenty hours.The reaction mixture was cooled to room temperature, pushed through aplug of celite and evaporated to a dark oil under a stream of nitrogen.The residue was triturated with 15 mL of ice water then air driedovernight giving 17.2 mgs (35.4% yield) of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoic acid as a white solid. The LC/MS data was obtained on a Shimadzuanalytical LC/Micromass Platform LC (ESI+) at 220 nm using the followingset of conditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with agradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroaceticacid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroaceticacid/10% HPLC grade acetonitrile), in 4 minutes with a 1 minute hold ata rate of 0.8 mL/minute. LCMS rt=2.770 min., m/z 438.3 (M+H), 93%purity.

5-(5-(tert-Butylcarbamoyl)-2-methoxyphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a 25 mL RBF was added3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methoxybenzoicacid (17.2 mg, 0.039 mmol), DMF (1 mL),N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.157 mmol),2-methylpropan-2-amine (0.012 mL, 0.118 mmol), and HATU,(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (59.8 mg, 0.157 mmol). The mixture wasstirred at room temperature under nitrogen overnight. The crude reactionwas diluted with 2 mL of acetonitrile and purified using a Shimadzupreparative HPLC employing acetonitrile/water/trifluoroacetic acid wheresolvent A was 10% acetonitrile/90% water/0.1% trifluoroacetic acid andsolvent B was 10% water/90% acetonitrile/0.1% trifluoroacetic acid witha Waters Sunfire C18 19×150 mm column at a gradient of 30-100% B and aflow rate of 25 mL/min. over 20 minutes with a 7 minute hold. Solventwas removed giving 15.7 mgs (80% yield) of5-(5-(tert-butylcarbamoyl)-2-methoxyphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamideas a white solid. The LC/MS data was obtained on a Shimadzu analyticalLC/Micromass Platform LC (ESI+) at 220 nm using the following set ofconditions: Phenomenex Luna 3 μm C18, 2×50 mm column, with a gradient of0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10%HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10%HPLC grade acetonitrile), in 4 minutes with a 1 minute hold at a rate of0.8 mL/minute. HPLC purity was determined using a Shimadzu analytical LCat 254 nm and 256 nm with a Waters Sunfire C18 3.5 μm 4.6×150 mm columnemploying water/acetonitrile/0.1% trifluoroacetic acid with a gradientof 10-100% B (B=95% HPLC grade acetonitrile/0.1% trifluoroacetic acid/5%HPLC grade water), (A=95% HPLC grade water/0.1% trifluoroacetic acid/5%HPLC grade acetonitrile), in 10 minutes with a 10 minute hold at a rateof 1 mL/minute. The HPLC purity was then confirmed with an orthogonalsolvent system and column using a Shimadzu analytical LC with a WatersXBridge Phenyl C18 3.5 μm 4.6×150 mm column employing water/methanol/10mM ammonium bicarbonate with a gradient of 10-100% B (B=95% HPLC grademethanol/10 mM ammonium bicarbonate/5% HPLC grade water), (A=95% HPLCgrade water/10 mM ammonium bicarbonate/5% HPLC grade methanol), in 10minutes with a 10 minute hold at a rate of 1 mL/minute. ¹H NMR (400 MHz,THF-d8) δ ppm 1.42 (s, 9H), 2.87 (d, J=4.77 Hz, 3H), 3.79 (s, 3H), 6.92(s, 1H), 7.06 (d, J=8.53 Hz, 1H), 7.17-7.30 (m, 3H), 7.39 (d, J=8.28 Hz,1H), 7.71-7.77 (m, 2H), 7.87 (dd, J=8.78, 2.26 Hz, 1H), 8.03-8.12 (m,2H). LCMS m/z 493.4 (M+H), rt=3.281 min. HPLC (Sunfire C18) rt=14.257min, 98.7% purity and (XBridge Phenyl C18) rt=14.852 min., 98.8% purity.

The procedures which follow utilize the methods as described within

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methylisoxazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methylisoxazol-3-yl)cyclopropanamine(0.074 g, 0.5 mmol, 1.1 eq), HOBT (0.094 g, 0.69 mmol, 1.5 eq), EDC.HCl(0.0.13 g, 0.69 mmol, 1.5 eq), in DCM at ambient temperature and under anitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol,3.0 eq). The clear mixture was stirred at ambient temperature for 12 h.The mixture was concentrated, diluted with water and extracted withEtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was purified byPreparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml). Yield: 0.1 g(39.22%). 1H NMR (400 MHz, CD₃OD): δ 1.39-1.48 (m, 4H), 2.36 (s, 3H),2.380-2.382 (d, 3H, J=0.8 Hz), 2.96 (s, 3H,), 4.05, (s, 3H), 6.05 (d,1H, J=0.8 Hz), 7.12 (s, 1H), 7.26-7.34 (m, 3H), 7.58-7.59 (d, 1H, J=1.2Hz), 7.62-7.64 (d, 1H, J=8.8 Hz), 7.81 (s, 1H), 7.96-7.98 (m, 2H). LCMS:(ES+) m/z=554.2 (M+H)⁺ Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 2.054, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 19.86    -   Wavelength: 220 nm, RT min: 19.86

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.976    -   Wavelength: 220 nm, RT min: 17.976

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(4-methyloxazol-5-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 0.46 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine(0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl(0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under anitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol,3.0 eq). The clear mixture was stirred at ambient temperature for 12 h.The mixture was concentrated, diluted with water and extracted withEtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was purified byPreparative TLC (Eluent Hexane:Ethyl acetate 1:1, 300 ml). Yield: 0.020g (8.3%).

1H NMR (400 MHz, CD₃OD): δ 1.31-1.40 (m, 4H), 2.28 (s, 3H), 2.35 (s,3H), 2.96 (s, 3H), 4.04 (s, 3H), 7.11 (s, 1H), 7.26-7.34 (m, 3H),7.575-7.578 (d, 1H, J=1.2 Hz), 7.62-7.64 (d, 1H, J=8.4 Hz), 7.76 (s,1H), 7.97-8.0 (m, 3H).

LCMS: (ES+) m/z=554.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.995, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 1 10 26 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.553    -   Wavelength: 220 nm, RT min: 18.553

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.866    -   Wavelength: 220 nm, RT min: 16.866

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyloxazol-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine(0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl(0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under anitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol,3.0 eq). The clear mixture was stirred at ambient temperature for 12 h.The mixture was concentrated, diluted with water and extracted withEtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was purified byCombiflash column chromatography (4 g flash column, CV 4.8 ml, 18ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.030 g(11.76%). 1H NMR (400 MHz, CD₃OD): δ 1.43-1.46 (m, 2H), 1.61-1.65 (m,2H), 2.29 (d, 3H, J=0.8 Hz), 2.37 (s, 3H), 2.96 (s, 3H), 4.06 (s, 3H),6.69 (s, 1H,), 7.14 (s, 1H), 7.28 (apparent t, 2H), 7.34 (dd, 1H, J=1.6,8.4 Hz), 7.59 (d, 1H, J=1.2 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.88 (s, 1H),7.96-8.00 (m, 2H). LCMS: (ES+) m/z=554.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 2.043, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 2 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.681    -   Wavelength: 220 nm, RT min: 18.681

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.000    -   Wavelength: 220 nm, RT min: 17.000

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyloxazol-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine(0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl(0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under anitrogen atmosphere was added diisopropylethylamine (0.19 ml, 1.3 mmol,3.0 eq). The clear mixture was stirred at ambient temperature for 12 h.The mixture was concentrated, diluted with water and extracted withEtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was purified byCombiflash column chromatography (4 g flash column, CV 4.8 ml, 18ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.045 g(17.6%) 1H NMR (400 MHz, DMSO-d₆): δ 1.11-1.14 (m, 2H), 1.20-1.23 (m,2H), 2.29 (s, 3H), 2.31 (s, 3H), 2.82 (d, 3H, J=4.4 Hz), 3.95 (s, 3H),7.12 (s, 1H), 7.33 (dd, 1H, J=1.6, 8.4 Hz), 7.40 (apparent t, 2H, J=8.8Hz), 7.49 (d, 1H, J=1.2 Hz), 7.60 (s, 1H), 7.72 (d, 1H, J=8.4 Hz),7.97-8.01 (m, 2H), 8.04 (s, 1H), 8.46-8.48 (m, 1H), 8.67 (s, 1H).

LCMS: (ES+) m/z=554.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.931, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 3 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.891    -   Wavelength: 220 nm, RT min: 18.891

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.019    -   Wavelength: 220 nm, RT min: 17.019

Methyl 2-Formamidoacetate

To an ethylformate (110 g, 148 mmol, 9.3 eq) solution containing glycinemethyl ester hydrochloride (20.0 g, 159 mmol, 1 eq)) was added PTSA (20mg) and the solution was brought to boil. Boiling TEA (17.69 g, 175mmol, 1.1 eq) was added dropwise and the reaction mixture was refluxedovernight. The reaction mixture was then cooled to room temperature. Awhite TEA salt was filtered and the filtrate was concentrated to afforda light brown liquid. The crude product was purified by silica gel(230-400) column chromatography using 50% EtOAc/hexane to EtOAc aseluent. Yield: 20 g (85%). ¹H NMR (400 MHz, CDCl₃): δ 3.7 (s, 3H), 4.04(d, 2H, J=5.6 Hz), 6.88 (s, 1H), 8.20 (s, 1H).

LCMS: (ES+) m/z=118 (M+H)⁺

ATLANTIS C18 (5.0×4.6-5.0 μm)

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B: MeCN    -   Flow: 5 ml/Min

Time % A % B 0.0 95.0 5.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.0 7.0 5.095.0

-   -   RT min: 2.115    -   Wavelength: 220 nm

Methyl isocyanoacetate. To the solution of Methyl 2-Formamidoacetate(10.0 g, 85 mmol, 1 eq) and TEA (21.58 g, 213 mmol, 2.5 eq) in methylenechloride at 0° C. was added POCl₃ (13.06 g, 85 mmol, 1 eq) dropwise. Thesolution turned red immediately. After all addition of the POCl₃ thereaction mixture was stirred for an additional 1 h at room temperature.To the reaction mixture was slowly added a Na₂CO₃ solution. The reactionmixture was stirred for 30 min. The organic phase was separated fromaqueous phase, washed with saturated NaCl solution and dried over K₂CO₃.The resultant solution was filtered and the filtrate was evaporatedunder reduced pressure to give a dark brown oil. The compound was usedwith out further purification. Yield: 7.0 g (70%). ¹H NMR (400 MHz,CDCl₃): δ 3.80 (s, 3H), 4.23 (s, 2H).

Methyl 5-methyoxazole-4-carboxylate

A stirred mixture of methyl isocyanoacetate (7.0 g, 70 mmol, 1 eq) andDBU (10.06 g, 70 mmol, 1 eq) in THF was cooled to 0° C., and a solutionof acetic anhydride (7.14 g, 70 mmol, 1 eq) in THF was added dropwiseover 15 min. The reaction mixture was stirred for 12 h at roomtemperature. The solvent was removed by Rota-vapor and water was added.The mixture was extracted with EtOAc. The crude product was purified bysilica gel (230-400) column chromatography using 30% EtOAc/hexane.Yield: 6.8 g (98%). ¹H NMR (400 MHz, CDCl₃): δ 2.54 (s, 3H), 3.80 (s,3H), 7.69 (s, 1H).

LCMS: (ES+) m/z=142 (M+H)⁺

Method: Column: Chromolith SpeedRod C18 (4.6×30) mm, 5 micron

-   -   Mphase A: 10% MeOH-90% H₂O-0.1% TFA    -   Mphase B: 90% MeOH-10% H₂O-0.1% TFA    -   Flow: 5 ml/min

Time (min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 0.629    -   Wavelength: 220 nm

5-Methoxyoxazole-4-carboxamide

A mixture of NH₄OH (50 mL) and methyl 5-methyoxazole-4-carboxylate (7.8g, 50 mmol, 1 eq) in a pressure tube was stirred at room temperature for12 h. Water was then added to the reaction mixture, which was extractedwith DCM to give the product. Yield: 4.1 g (47%). ¹H NMR (400 MHz,CDCl₃): δ 2.66 (s, 3H), 5.68 (s, 1H), 6.81 (s, 1H), 7.68 (s, 1H). LCMS:(ES+) m/z=127 (M+H)⁺

Method: Column: Chromolith SpeedRod C18 (4.6×30)mm, 5 micron

-   -   Mphase A: 10% MeOH-90% H₂O-0.1% TFA    -   Mphase B: 90% MeOH-10% H₂O-0.1% TFA Flow: 5 ml/min

Time(min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 0.365    -   Wavelength: 220 nm

5-methyloxazole-4-carbonitrile

5-Methoxyoxazole-4-carboxamide (2.1 g, 16 mmol, 1 eq) was dissolved inpyridine (30 mL) and treated with POCl₃ (3.8 g, 25 mmol, 1.5 eq). Theresultant slurry which turned to a brown solution was stirred for 5 h atroom temperature. The reaction mixture was diluted with ice and theaqueous layer was adjusted to pH 3 with 6M HCl. The mixture wasextracted with ether. The organic layer was separated and washed withwater, brine, dried to give the product. Yield: 0.4 g (30%). ¹H NMR (400MHz, CDCl₃): δ 2.53 (s, 3H), 7.79 (s, 1H).

LCMS: (ES+) m/z=109.2 (M+H)⁺

Column: Chromolith speed Rod C18 (4.6×30)mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT: 0.780    -   Wavelength: 220 nm

1-(5-methyloxazole-4-yl)cyclopropanamine

5-methyloxazole-4-carbonitrile (0.9 g, 8.3 mmol, 1 eq) was dissolved indry THF at room temperature, and titanium(IV) isopropoxide (2.84 g, 10mmol, 1.2 eq) was added dropwise over a period of 15 minutes. Theresulting mixture was stirred for 10 min and ethyl magnesium bromide(2.75 g, 2.5 eq) was added dropwise and slowly at ambient temperature,and the reaction was stirred for 1 h. BF₃.etherate (2.84 g, 20 mmol, 2.5eq) was then added slowly at ambient temperature and the above mixturewas stirred at ambient temperature for 3 h. Water was then added to themixture and the pH was brought to 10 using 10% sodium hydroxidesolution. The reaction mixture was extracted with dichloromethane,concentrated and purified by Combiflash chromotagraphy. Yield: 0.6 g(65%). ¹H NMR (400 MHz, CDCl₃): δ 0.89 (t, J=4 Hz, 2H), 0.93 (t, J=4 Hz,2H), 2.18 (s, 2H), 2.36 (s, 3H), 7.61 (s, 1H). LCMS: (ES+) m/z=138.7(M)⁺

Column: ATLANTIS C18 50×4.6 mm 5 μm

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B MeCN    -   Flow: 1.0 ml/min

Time (min) % B % A 0.0 5.0 95.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.07.0 5.0 95.0

-   -   RT: 2.763    -   Wavelength: 220 nm

Ethyl 4-methyloxazole-5-carboxylate

Ethyl 2-chloro-3-oxobutanoate (10 g, 254 mmoles, 1 eq) was dissolved informamide (8.4 ml) and the reaction was stirred at 120° C. for 12 hours.The reaction mixture was then cooled to 0° C., added with water andextracted with ethyl acetate. The organic layer was separated and washedwith brine and the product was purified by column chromatography (eluent100% ethyl acetate), Yield: 7.9 g (85%). ¹H NMR (400 MHz, CDCl₃): δ1.34-1.37 (t, 3H, J=7.2 Hz), 2.45 (s, 3H), 4.32-4.38 (q, 2H, J=7.2 Hz),7.85 (s, 1H). LCMS: (ES+) m/z=156.2 (M+H)⁺

Column: XBRIDGE C18 (4.6×30) mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT: 0.892, Wavelength 220 nm

4-methyloxazole-5-carboxamide

A mixture of ethyl 4-methyloxazole-5-carboxylate (7.8 g, 50 mmoles) andammonium hydroxide in a seal tube was stirred at rt for 12 hours. Aftercompletion of the reaction, solid was filtered and washed with water.The aqueous was extracted with ethyl acetate. The organic extract wasdried and concentrated and combined with the filtered solid. Yield: 4.1g (47%) ¹H NMR (400 MHz, CDCl₃): δ 2.38 (s, 3H), 7.92 (s, 1H). LCMS:(ES+) m/z=126.7 (M)⁺

ATLANTIS C18 (5.0×4.6-5.0 μm)

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B: MeCN    -   Flow: 5 ml/Min

Time % A % B 0.0 95.0 5.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.0 7.0 5.095.0

-   -   RT min: 1.666    -   Wavelength: 220 nm

4-methyloxazole-5-carbonitrile

4-methyloxazole-5-carboxamide (2.1 g, 16 mmoles, 1 eq) was dissolved inpyridine (30 ml) and treated with POCl₃ (2.31 ml 25 mmoles, 1.5 eq), andthe reaction was stirred at room temperature for 5 hours. The reactionwas then diluted with ice, and aqueous layer was adjusted to pH3 with 6MHCl and extracted with diethyl ether. The organic layer was separatedand washed with water, brine and dried to give the product. Yield: 0.4 g(30%) ¹H NMR (400 MHz, CDCl₃): δ 2.52 (s, 3H), 7.79 m (s, 1H). LCMS(ES+) m/z=109.1 (M+H)⁺

Column: Chromolith speed Rod C18 (4.6×30)mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT min: 0.775    -   Wavelength: 220 nm

1-(4-methyloxazol-5-yl)-cyclopropanamine

4-Methyloxazole-5-carbonitrile (0.4 g, 3.7 mmole. 1 eq) was dissolved indry THF, and added with titanium isopropoxide (1.32 g, 4.4 mmole, 1.2eq) dropwise over 15 minutes. A solution of ethylmagnesium bromide (1.23g, 9.3 mmole, 2.5 eq) in THF was added at rt over 15 minutes, and thereaction was stirred at rt for 1 hour. BF3 etherate (0.63 g, 4.4 mmole,1.2 eq) was then added and the mixture stirred at rt for 1 hour, Afterwhich, 1N NaOH solution was added to adjust the pH to 9-10. The reactionmixture was passed through celite and washed with ethyl acetate. Theorganic layer was washed with brine, concentrated and purified by columnchromatography yielding 0.3 g (78%) of the product. ¹H NMR (400 MHz,CDCl₃): δ 0.91 (t, J=4 Hz, 2H), 0.96 (t, J=4 Hz, 2H), 2.18 (s, 2H), 2.06(s, 3H), 7.64 (s, 1H). LCMS (ES+) m/z=138.8 (M)⁺

Column: ATLANTIS C18 50×4 6 mm 5 μm

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B MeCN    -   Flow: 1.0 ml/min

Time (min) % B % A 0.0 5.0 95.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.07.0 5.0 95.0

-   -   RT min: 2.781    -   Wavelength: 220 nm

N-acetyl-N-(2-oxopropyl)acetamide

A mixture of Glycine (5 g, 66 mmole, 1 eq), pyridine 32.4 ml, 401 mmole,6 eq) and acetic anhydride (50 ml, 532 mmole, 8 eq) was heated to refluxfor 12 hours. The mixture was then concentrated under reduced pressureand purified by column chromatography (eluent Hexane:ethyl acetate 50%).Yield 3 g (57%) ¹H NMR (400 MHz, CDCl₃): δ 2.21 (s, 3H), 2.32 (s, 6H),4.49 (s, 2H). LCMS: (ES+) m/z=158 (M)⁺

Method: Column: Chromolith SpeedRod C18 (4.6×30) mm, 5 micron

-   -   Mphase A: 10% MeOH-90% H₂O-0.1% TFA    -   Mphase B: 90% MeOH-10% H₂O-0.1% TFA Flow: 5 ml/min

Time(min.) % A % B 0.0 100.0 0.0 2.0 0.0 100.0 3.0 0.0 0.0

-   -   RT min: 0.375    -   Wavelength: 220 nm

1-aminopropan-2-one

N-acetyl-N-(2-oxopropyl)acetamide (50 g, 318 mmole) was dissolved in amixture of conc.HCl (150 ml) and water (150 ml), and the reactionmixture was heated to reflux under a nitrogen atmosphere for 6 hours.The reaction mixture was then concentrated and the dark red oily residuewas taken to the next step. (Crude Yield: 46 g).

Methyl 2-oxo-2-(2-oxopropylamino)acetate

Methoxy oxalyl chloride (173 ml, 1890 mmole, 3 eq) was added dropwise toa suspension of 1-aminopropan-2-one hydrochloride (946 g, 630 mmole, 1eq) in benzene, and the resulting mixture heated to reflux for 4 hours.After evaporation of benzene, the residue was made alkaline with 3NNa₂CO₃ and extracted with chloroform. The crude product was taken to thenext step. (Crude Yield: 47 g).

Methyl 5-methyloxazole-2-carboxylate

A mixture of methyl 2-oxo-2-(2-oxopropylamino)acetate (47 g, 296 mmole,1 eq) and in POCl₃ (400 mL) was refluxed for 3 hours. After evaporation,the mixture was poured into ice water. The aqueous was made alkalinewith K₂CO₃ and extracted with CHCl₃ and purified by columnchromatography. Yield: 27 g (40%) ¹H NMR (400 MHz, CDCl₃): δ 2.40 (s,3H), 3.96 (s, 3H), 6.96 (s, 1H). LCMS: (ES+) m/z=142.2 (M+H)⁺

Column: XBRIDGE C18 (4.6×30) mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT min: 0.922, Wavelength 220 nm

Methyl 5-methyloxazole-2-carboxamide

A mixture of methyl 5-methyloxazole-2-carboxylate (26 g, 184 mmoles) andammonium hydroxide (400 ml) in a sealed tube was stirred at rt for 12hours. After completion of the reaction, solid was filtered and washedwith water. The aqueous layer was extracted with ethyl acetate. Theorganic extract was dried, concentrated and combined with the filteredsolid. Yield (23 g, 82%) ¹H NMR (400 MHz, CDCl₃): δ 2.40 (s, 3H), 6.14(s, 1H), 6.85 (s, 1H), 6.96 (s, 1H). LCMS (ES+) m/z=127.0 (M+H)⁺

Column: Chromolith speed ROD C18 (4.6×30) mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-0.1% TFA    -   Mphase B: 90% MeOH-10% H₂O-0.1% TFA    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT min: 0.268, Wavelength 220 nm

Methyl 5-methyloxazole-2-carbonitrile

5-methyloxazole-2-carboxamide (5 g, 39.7, 1 eq) was dissolved inpyridine (75 ml) and treated with POCl₃ (5.51 ml, 59.5 mmoles, 1.5 eq),and the reaction was stirred at rt for 5 hours. The reaction mixture wasdiluted with ice-water, and the pH of the aqueous was adjusted to 3using 6M HCl and extracted with diethyl ether. The organic layer waswashed with water, brine and dried to give the product. Yield: 4 g (80%)¹H NMR (400 MHz, CDCl₃): δ2.09 (s, 3H), 6.62 (s, 1H). LCMS (ES+)m/z=109.3 (M+H)⁺

Column: Chromolith speed Rod C18 (4.6×30)mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT min: 0.777    -   Wavelength: 220 nm

1-(5-methyloxazol-2-yl)-cyclopropanamine

5-methyloxazole-2-carbonitrile (2 g, 18 mmole. 1 eq) was dissolved indry THF, and titanium isopropoxide (6.31 g, 22.2 mmole, 1.2 eq) wasadded dropwise over 15 minutes. A solution of ethyl magnesium bromide(6.15 g, 46.25, 2.5 eq) in THF was added at rt over 15 minutes, and thereaction mixture was stirred at rt for 1 hour. BF₃ etherate (6.5 g,46.25, 1.2 eq) was then added and the mixture stirred at rt for 1 hour.1N NaOH solution was added to the mixture to adjust the pH to 9-10. Thereaction mixture was passed through celite and washed with ethylacetate. The organic layer was washed with brine, concentrated andpurified by column chromatography to yield 0.5 g of the product. ¹H NMR(400 MHz, CDCl₃): δ ¹H NMR (400 MHz, CDCl₃): δ 0.76 (t, J=4 Hz, 4H),2.17 (s, 3H), 7.31 (s, 1H). LCMS: (ES+) m/z=138.9 (M+H)⁺

Column: ATLANTIS C18 50×4.6 mm 5 μm

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B MeCN    -   Flow: 1.0 ml/min

Time (min) % B % A 0.0 5.0 95.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.07.0 5.0 95.0

-   -   RT min: 2.813    -   Wavelength: 220 nm

5-methylthiazole-2-carbaldehyde

To a solution of BuLi (32 mL, 51 mmol, 1 eq, 1.6 M in hexane) in etherat −78° C. was added dropwise a solution of 5-methylthiazole (5 g, 50mol, 1 eq) in ether at −78° C. for 1.5 hours. A solution of DMF (5.8 mL,75 mmol, 1.5 eq) in ether was added at once, and the reaction wasallowed to warm to room temperature and stirred overnight. Ice was addedto the mixture followed by the slow addition of 4 N HCl. The mixture wasextracted with ether. The aq. layer was bought to pH 7.5 with solidNaHCO₃ and extracted with ether. The combined ethereal extracts weredried and concentrated to give a crude residue which was purified byflash chromatography on silica gel using 10% EtOAc/Hexane. Yield: 6.1 g¹H NMR (400 MHz, CDCl₃): δ 2.56 (s, 3H), 7.79 (s, 1H), 9.90 (s, 1H).LCMS: (ES+) m/z=128.2 (M+H)⁺

Column: Chromolith speed Rod C18 (4.6×30) mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT min: 0.767, Wavelength: 220 nm

5-methylthiazole-2-carbaldehyde oxime

To a solution of 5-methylthiazole-2-carbaldehyde (6.1 g, 48 mmol) inEtOH (30 mL), was added pyridine (4 mL, 49 mmol) and HONH₂.HCl (3.3 g,47 mmol). The mixture was stirred at ambient temperature for 12 hours.The reaction mixture was diluted with DCM and extracted with water. Theorganic solution was dried, filtered and concentrated to give the crudeoxime. Yield: 6 g LCMS: (ES+) m/z=143.8 (M+H)⁺

Column: ATLANTIS C18 50×4 6 mm 5 μm

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B MeCN    -   Flow: 1.0 ml/min

Time (min) % B % A 0.0 5.0 95.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.07.0 5.0 95.0

-   -   RT min: 3.624, Wavelength: 220 nm

5-methylthiazole-2-carbonitrile

5-Methylthiazole-2-carbaldehyde oxime (6 g, 42 mmol, 1 eq) was dissolvedin DCM (100 mL) and CDI (7.8 g, 48 mmol) was added portion-wise to thereaction mixture. The mixture was then stirred at rt overnight, addedwith water and extracted with DCM. The organic layer was dried andconcentrated to give a crude residue, which was purified by flashchromatography on silica gel using 10% EtOAc/Hexane. Yield: 3.2 g ¹H NMR(400 MHz, CDCl₃): δ 2.59 (s, 3H), 7.71 (s, 1H) LCMS: (ES+) m/z=125.2(M+H)⁺

Column: Chromolith speed Rod C18 (4.6×30)mm, 5 μm

-   -   Mphase A: 10% MeOH-90% H₂O-10 mM NH₄OAc    -   Mphase B: 90% MeOH-10% H₂O-10 mM NH₄OAc    -   Flow: 5 ml/min

Time (min): 0 2 3 % B: 0 100 0

-   -   RT min: 0.780, Wavelength: 220 nm

1-(5-methylthiazol-2-yl)cyclopropanamine

5-methylithizole-2-carbonitrile (1.0 g, 8 mmol, 1 eq) was dissolved inTHF. Ti(Oi-Pr)₄ (2.74 g, 9.6 mmol, 1.2 eq) was added dropwise over aperiod of 5-10 min and the reaction mixture was stirred at rt for 15min. The mixture was then cooled to 0° C. and EtMgBr (2.68 g, 10 mL, 20mmol, 2.5 eq, 2M in THF) was added dropwise over a period of 10-15 min.The mixture was stirred at 0° C. for 15 min. and then at ambienttemperature for 1 h. The mixture was cooled again to 0° C. and, BF₃.OEt₂(2.5 mmol) was added dropwise over a period of 5-10 min at 0° C. Afterthe mixture was stirred for 10 min at 0° C. and 1 h at ambienttemperature, 1 N NaOH was added at 0° C. DCM was added to the reactionmixture which was stirred for 5-10 min. The mixture was filtered throughcelite and washed with DCM. The organic layer was concentrated to give aresidue which was purified by flash chromatography on silica gel using10% chloroform/methanol. Yield: 0.6 g ¹H NMR (400 MHz, CDCl₃): δ 1.20(t, J=4 Hz, 2H) 1.31 (t, J=4 Hz, 2H), 2.40 (s, 3H), 7.26 (s, 1H). LCMS:(ES+) m/z=154.7 (M)⁺

Column: ATLANTIS C18 50×4 6 mm 5 μm

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B MeCN    -   Flow: 1.0 ml/min

Time (min) % B % A 0.0 5.0 95.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.07.0 5.0 95.0

-   -   RT min: 2.960, Wavelength: 220 nm

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methylthiazol-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine(0.093 g, 0.6 mmol, 1.2 eq), EDCI.HCl (0.103 g, 0.54 mmol, 1.1 eq), HOBT(0.067 g, 0.5 mmol, 1.5 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) weredissolved in dichloromethane and the mixture was stirred at roomtemperature for 18 h. The mixture was then added with water, and theorganic layer was separated and washed with water, and the product waspurified by preparative TLC. Yield: 25 mg (15%). ¹H NMR (400 MHz,DMSO-d₆): δ 1.34-1.37 (m, 2H), 1.50-1.53 (m, 2H), 2.31 (s, 3H), 2.35 (s,3H), 2.83-2.84 (d, J=4.8 Hz, 3H), 7.27 (d, J=1.2 Hz, 1H), 7.39-7.47 (m,4H), 7.60 (d, J=1.6 Hz, 1H), 7.76-7.78 (d, J=8.4 Hz 1H), 7.83-7.85 (m,2H), 8.02 (m, 2H), 8.45 (m, 1H), 9.51 (s, 1H) LCMS: (ES+) m/z=540 (M+H)⁺

Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 2.015, Wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.846    -   Wavelength: 220 nm, RT min: 18.846    -   Purity: 99.7%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Mobile Phase A: 0.05% TFA in water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:water (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.065    -   Wavelength: 220 nm, RT min: 17.065    -   Purity: 99.8%

1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine

1-methyl-1H-imidazole-4-carbonitrile (0.5 g, 4.6 mmol, 1 eq) wasdissolved in THF, and titanium isopropoxide (1.6 g, 5.6 mmol, 2.5 eq)was added dropwise over 15 minutes to the mixture, which was thenstirred for 15 minutes at room temperature. Ethyl magnesium bromide (1.6g, 6 mL, 12 mmol, 2.6 eq, 2M in THF) was added to the mixture at roomtemperature over 15 minutes, and the reaction mixture stirred for 1 h.BF₃ etherate (0.8 g, 5.6 mmol, 2.2 eq) was added and the reactionmixture stirred at room temperature for another 1 h. 1 N NaOH solutionwas added to the mixture to adjust the pH to 9-10. The reaction mixturewas filtered through celite and washed with DCM. The organic layer wasconcentrated to give a residue which was purified by flashchromatography on silica gel using 10% chloroform/methanol. Yield: 0.6 g¹H NMR (400 MHz, CDCl₃): δ 0.97 (t, J=3.4 Hz, 2H), 1.00 (t, J=3.4 Hz,2H), 3.63 (s, 3H), 7.28 (s, 1H), 7.31 (s, 1H). LCMS: (ES+) m/z=138.2(M+H)⁺

Column: ATLANTIS C18 50×4 6 mm 5 μm

-   -   Mphase A: 10 mM Ammonium acetate    -   Mphase B MeCN    -   Flow: 1.0 ml/min

Time (min) % B % A 0.0 5.0 95.0 4.0 95.0 5.0 5.5 95.0 5.0 6.0 5.0 95.07.0 5.0 95.0

-   -   RT min: 1.949, Wavelength: 220 nm

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(1-methyl-1H-imidazol-4-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.15 g, 0.37 mmol, 1 eq),1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2eq), EDCI.HCl (0.078 g, 0.40 mmol, 1.1 eq), HOBT (0.049 g, 0.37 mmol,1.0 eq) and TEA (0.15 ml, 1.1 mmol, 3 eq) were dissolved indichloromethane and the above mixture was stirred at room temperaturefor 18 h. The mixture was then added with water. The organic layer wasseparated, washed with water, concentrated and the crude productpurified by Prep. HPLC. Yield: 24.69 mg (10%). ¹HNMR (400 MHz, DMSO-d₆):δ 1.04-1.07 (m, 2H), 1.17-120 (m, 2H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz,3H), 3.54 (s, 3H), 6.7 (s, 1H), 7.37-7.43 (m, 5H), 7.58 (s, 1H),7.74-7.77 (d, J=8.8 Hz, 1H), 7.81-7.82 (m, 2H), 7.97-8.01 (m, 2H),8.46-8.47 (m, 1H), 9.06 (s, 1H) LCMS: (ES+) m/z=523.2 (M+H)⁺

Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% ACN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% ACN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.854, Wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 7.220    -   Wavelength: 220 nm, RT min: 7.220    -   Purity: 99.4%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 8.541    -   Wavelength: 220 nm, RT min: 8.541    -   Purity: 99.3%

1-(pyrimidin-5-yl)cyclopropaneamine

Pyrimidine-5-carbonitrile (5 g, 47.6 mmol, 1 eq) was taken in a dry THFunder an argon atmosphere. Titanium isopropoxide (17 ml, 57.1 mmol, 1.2eq) was then added slowly at ambient temperature and the resultingmixture was stirred for 15 mins. To the above stirred mixture was slowlyadded ethyl magnesium bromide (107 ml, 2.2 eq, 1 M in THF) via syringeat ambient temperature (during the addition of EtMgBr, the reactionmixture turned black). The reaction mass was stirred for an hour, andBF₃.EtO (16.7 ml, 135 mmol, 2.8 eq) was then added slowly throughsyringe to the mixture at 0° C. The reaction was then allowed to warm toambient temperature and the stirring was continued for another one hour.Finally the reaction was quenched by adding 50 ml of water, and thereaction mixture was passed through Celite and the bed washed with waterand ethyl acetate. The filtrate was basified with 10% NaOH solution(pH=9) and then extracted with DCM and washed with brine. The requiredproduct was purified by silica gel (60-120) column chromatography using4% methanol/DCM as the eluent. Yield: 0.1 g (5%) ¹H NMR (400 MHz,DMSO-d₆): δ 1.04-1.08 (m, 2H), 1.18-1.25 (m, 2H), 8.26 (d, 2H), 9.05 (s,1H). LCMS: (ES+) m/z=136 (M+H)⁺

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-5-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.074g, 0.55 mmol, 1.2 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved indichloromethane and the above mixture was stirred at room temperaturefor 18 h. The mixture was then added with water. The Organic layer wasseparated, washed with water, concentrated and the crude product waspurified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as aneluent. Yield: 50 mg (20%) ¹HNMR (400 MHz, DMSO-d₆): δ 1.33-1.36 (m,2H), δ 1.42-1.45 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, J=4.4 Hz, 3H),3.96 (s, 3H), 7.14 (s, 1H), 7.33 (dd, J=1.6, 8.4 Hz, 1H), 7.40 (t,J=8.8, 2H), 7.50 (d, J=1.2 Hz, 1H), 7.52 (s, 1H), 7.72 (d, J=8.4 Hz,1H), 7.97-8.01 (m, 2H), 8.47 (q, J=4.4 Hz, 1H), 8.67 (s, 2H), 8.91 (s,1H), 9.00 (s, 1H) LCMS: (ES+) m/z=551.2 (M+H)⁺

LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.87, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 1 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.45    -   Wavelength: 220 nm, RT min: 10.45    -   Purity: 98.6%

: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.78    -   Wavelength: 220 nm, RT min: 9.78    -   Purity: 98.5%

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methyloxazol-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine(0.082 g, 0.6 mmol, 1.1 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT(0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) weredissolved in dichloromethane and the above mixture was stirred at roomtemperature for 18 h. The mixture was then added with water. The organiclayer was separated, washed with water and concentrated to give thecrude product which was purified by Prep. TLC (20 mm thickness) using 5%methanol/DCM as an eluent. Yield: 25 mg (25%) ¹HNMR (400 MHz, DMSO-d₆):δ 1.25-1.28 (m, 2H), 1.40-1.44 (m, 2H), 2.21 (d, J=1.2 Hz, 3H), 2.29 (s,3H), 2.82 (d, J=4.8, 3H), 6.66 (d, J=1.2 Hz, 1H), 7.38-7.44 (m, 4H),7.57 (d, J=1.2, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.81-7.83 (s and m, 2H),7.98-8.01 (m, 2H), 8.47 (q, J=4.8 Hz, 1H), 9.28 (s, 1H). LCMS: (ES+)m/z=524.2 (M+H)⁺

Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.953, Wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.817    -   Wavelength: 220 nm, RT min: 17.817    -   Purity: 99.3%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:ACN (95:5)    -   Mobile Phase B: 0.05% TFA in ACN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.386    -   Wavelength: 220 nm, RT min: 16.386    -   Purity: 99.4%

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methyloxazol-4-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine(0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq),HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) weredissolved in dichloromethane and the above mixture was stirred at roomtemperature for 18 h. The mixture was then added with water. The organiclayer was separated, washed with water and concentrated to give thecrude product which was purified by Prep. TLC (20 mm thickness) using 5%methanol/DCM as an eluent. Yield: 25 mg (25%) ¹HNMR (400 MHz, DMSO-d₆):δ 1.11 (m, 2H), 1.20-1.22 (m, 2H), 2.28 (s, 3H), 2.29 (s, 3H), 2.82 (d,J=4.4 Hz, 3H), 7.38-7.42 (m, 4H), 7.57 (s, 1H), 7.74-7.81 (m, 3H), 8.04(s, 1H), 7.97-8.01 (m, 2H), 8.45-8.46 (m, 1H), 9.16 (s, 1H). LCMS: (ES+)m/z=524.2 (M+H)⁺

Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.92, Wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.085    -   Wavelength: 220 nm, RT min: 18.085    -   Purity: 95%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.398    -   Wavelength: 220 nm, RT min: 16.398    -   Purity: 95%

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(4-methyloxazol-5-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.2 g, 0.5 mmol, 1 eq), 1-(4-methyloxazol-5-yl)cyclopropanamine(0.103 g, 0.74 mmol, 1.2 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq),HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) weredissolved in dichloromethane and the above mixture was stirred at roomtemperature for 18 h. The mixture was then added with water. The organiclayer was separated, washed with water and concentrated to give thecrude product which was purified by Prep. HPLC. Yield: 25 mg (25%) ¹HNMR(400 MHz, DMSO-d₆): δ 1.21 (broad s, 4H), 2.17 (s, 3H), 2.28 (s, 3H),2.83 (d, J=4.8 Hz, 3H), 7.37-7.43 (m, 4H), 7.56 (d, J=1.6 Hz, 1H),7.74-7.79 (m, 3H), 7.98-8.02 (m, 2H), 8.0 (s, 1H), 8.44-8.45 (m, 1H),9.20 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)⁺

Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.913, Wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.45    -   Wavelength: 220 nm, RT min: 17.45    -   Purity: 95%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.01    -   Wavelength: 220 nm, RT min: 16.01    -   Purity: 95%

Preparative HPLC Method

Column: Symmetry C18 (19×250×10μ)

-   -   Mobile Phase: 0.1% TFA (A), MeCN (B)    -   Gradient:

Time Flow A B 0 15 ml/min 70 30 10 15 ml/min 30 70

-   -   RT: 16.9 min.

5-(5-(1-(4,6-Dimethylpyrimidin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.2 g, 0.5 mmol, 1 eq),1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.203 g, 1.2 mmol, 2.5eq) (60% purity), HOBT (0.068 g, 0.5 mmol, 1.1 eq), EDC.HCl (0.105 g,0.55 mmol, 1.1 eq) in DCM at ambient temperature under a nitrogenatmosphere was added diisopropylethylamine (0.194 g, 1.5 mmol, 3 eq).The clear mixture was stirred at ambient temperature for 12 h. Themixture was concentrated, diluted with water and extracted with EtOAc.The organic layer was further washed with water, dried over sodiumsulphate and concentrated. The product obtained was further purified bycolumn chromatography (neutral alumina) using 0.5% Methanol/DCM andfinally purified by preparative HPLC. Yield: 0.15 g (14%). ¹H NMR (400MHz, DMSO-d₆): δ 1.24-1.27 (m, 2H), 1.53-1.56 (m, 2H), 2.30 (s, 3H),2.32 (s, 6H), 2.82 (d, J=4.8 Hz, 3H), 7.00 (s, 1H), 7.38-7.44 (m, 4H),7.59 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.82-7.84 (s and d, 2H),7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 9.14 (s, 1H). LCMS: (ES+)m/z=549.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0 3.6 100.0 0.0

-   -   RT min: 1.995, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 4 10 27 100 30 100

-   -   Wavelength: 254 nm, RT min: 10.742    -   Wavelength: 220 nm, RT min: 10.742    -   Purity: 99%

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 10.297    -   Wavelength: 220 nm, RT min: 10.297    -   Purity: 99%

5-(5-(1-(4,6-dimethylpyrimidin-2-yl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.15 g, 0.34 mmol, 1 eq),1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.17 g, 0.1 mmol, 3 eq)(60% purity), HOBT (0.046 g, 0.34 mmol, 1.0 eq), EDC.HCl (0.072 g, 0.37mmol, 1.1 q) in DCM at ambient temperature under a nitrogen atmospherewas added diisopropylethylamine (0.132 g, 1.0 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was further purified by columnchromatography (neutral alumina) using 0.5% Methanol/DCM and finallypurified by preparative HPLC. Yield: 0.15 g (14%). ¹H NMR (400 MHz,DMSO-d₆): δ 1.43-1.44 (d, J=3.36 Hz, 2H), 1.51-1.54 (d, J=3.48 Hz, 2H),2.32-2.34 (d, J=5.8 Hz, 9H), 2.81-2.82 (d, J=4.6 Hz, 3H), 4.0 (s, 3H)7.0 (s, 1H), 7.15 (s, 1H), 7.34-7.42 (m, 3H), 7.52 (s, 1H), 7.72-7.74(d, J=8.8 Hz, 2H), 7.97-8.02 (m, 2H), 8.46-8.48 (d, J=4.56 Hz, 1H), 8.91(s, 1H). LCMS: (ES+) m/z=579.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 2.133, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 5 10 28 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.09    -   Wavelength: 220 nm, RT min: 18.09    -   Purity: 99.9%

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.68    -   Wavelength: 220 nm, RT min: 16.68    -   Purity: 99.9%

1-(pyrazin-2-yl)cyclopropanecarbonitrile

A mixture of 2-fluoropyrazine (2.0 g, 20.4 mmol, 1 eq) andcyclopropanecarbonitrile (1.5 ml, 20.4 mmol, 1 eq) In a dry flask underan argon atmosphere were dissolved in dry toluene (50 ml). The solutionwas cooled to 0° C. and potassium bis(trimethylsilyl)amide (0.5 M intoluene, 40.9 ml, 20.45 mmol, 1 eq) was added slowly over 5 min viasyringe. The black, opaque reaction mixture was allowed to warm to roomtemperature and stirred for 4 h. The reaction was diluted with water(200 ml) and ethyl acetate (200 ml), and the layers were separated. Theaqueous layer was back extracted with ethyl acetate (2×100 ml). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to give a black oil. The crude was purified by silica gel(60-120) column chromatography using 20% ethyl acetate in hexane aseluent to give 0.25 g of the product as light a yellow oil. Yield: 0.25g (8.4%). ¹H NMR (400 MHz, CD₃OD): δ 1.84-1.86 (m, 4H), 8.51-8.55 (q,2H), 8.89 (s, 1H). LCMS: (ES+) m/z=146.2 (M)⁺

Method: Column: PUROSPHER@star rp-18 (4.6×30)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAC in 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAC in 10% H₂O, 90% MeCN    -   Flow: 2.5 ml/min

Time % B 0.0 0.0 2.0 100.0 2.5 100.0 3.0 0.0

-   -   RT min: 1.063, wavelength: 220 nm

1-(pyrazin-2-yl)cyclopropanecarboxylic acid

1-(Pyrazin-2-yl)cyclopropanecarbonitrile (0.25 g, 1.72 mmol, 1 eq) wasdissolved in MeOH (5 ml) and NaOH solution (20 wt % in water, 2.0 ml)was added via syringe in one portion. The orange mixture was heated to75° C. for 22 h., cooled to room temperature, and acidified to pH 2-3with 6N HCl. The mixture was filtered through a pad of celite with MeOHwash and the filtrate was concentrated. The residue was suspended inethyl acetate, dried with Na2SO4, filtered and concentrated to give theproduct as an orange solid. Yield: 0.18 g (64%) ¹H NMR (400 MHz,DMSO-d₆): δ 1.42-1.45 (m, 2H), 1.54-1.56 (m, 2H), 8.48-8.53 (m, 2H),8.86-8.87 (d, 1H, J=1.6 Hz), 12.58 (s, 1H). LCMS: (ES+) m/z=165.2 (M+H)⁺

Column: PUROSPHER@star rp-18 (4.6×30)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAC in 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAC in 10% H₂O, 90% MeCN    -   Flow: 2.5 ml/Min

Time % B 0.0 0.0 2.0 100.0 2.5 100.0 3.0 0.0

-   -   RT min: 0.206, wavelength: 220 nm

allyl 1-(pyrazin-2-yl)cyclopropylcarbamate

To a solution of 1-(pyrazin-2-yl)cyclopropanecarboxylic acid (0.18 g,1.09 mmol, 1 eq) in dry toluene (5 ml) was added TEA (0.18 ml, 1.3 mmol,1.2 eq) followed by diphenylphosphoryl azide (0.25 ml, 1.18 mmol, 1.08eq). The reaction was stirred for 1 h at r.t. Allyl alcohol (0.36 ml,5.30 mmol, 4.9 eq) was added via syringe and the reaction was heated to90° C. for 3 h. After cooling to room temperature, the reaction mixturewas diluted with water (10 ml) and ethyl acetate (10 ml). The layerswere separated and the water layer was extracted with ethyl acetate(2×10 ml). The combined organic layers were dried over Na₂SO₄ andconcentrated to give a black residue that was purified by silica columnchromatography using 20-30% ethyl acetate in hexane. Yield: 0.12 g(50%). ¹H NMR (400 MHz, CD₃OD): δ 1.31-1.38 (m, 2H), 1.60-1.63 (m, 2H),4.60-4.61 (d, J=5.2 Hz, 2H), 5.23-5.26 (d, J=10.4 Hz, 1H), 5.35-5.39 (d,J=17.2 Hz, 1H,), 5.96-6.03 (m, 1H), 8.36-8.36 (d, J=2.4 Hz, 1H),8.49-8.508 (q, 1H), 8.63 (s, 1H). LCMS: (ES+) m/z=220.2 (M+H)⁺

Column: PUROSPHER@star rp-18 (4.6×30)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAC in 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAC in 10% H₂O, 90% MeCN    -   Flow: 2.5 ml/Min

Time % B 0.0 0.0 2.0 100.0 2.5 100.0 3.0 0.0

-   -   RT min: 1.180, wavelength: 220 nm

1-(pyrazin-2-yl)cyclopropanamine

To a solution of allyl 1-(pyrazin-2-yl)cyclopropylcarbamate (0.12 g,0.547 mmol, 1 eq) and morpholine (0.47 ml, 5.47 mmol, 10 eq) in THF (3ml) was added Pd(PPh₃)₄ (0.038 g, 0.033 mmol, 0.06 eq), and the yellowmixture was stirred at 50° C. for 3 h. The solvent was removed under astream of N2 and the residue was purified by flash chromatography using4-7% of methanol in dichloromethane to give the compound as a yellowoil. Yield: 0.05 g (68.5%). ¹H NMR (400 MHz, CD₃OD): δ 1.17-1.20 (m,2H), 1.36-1.38 (m, 2H), 8.36-8.37 (d, J=2.4 Hz, 1H), 8.49-8.50 (q, 1H),8.85-8.85 (d, J=1.6 Hz, 1H). LCMS: (ES+) m/z=136.2 (M+H)⁺

Column: PUROSPHER@star rp-18 (4.6×30)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAC in 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAC in 10% H₂O, 90% MeCN    -   Flow: 2.5 ml/Min

Time % B 0.0 0.0 2.0 100.0 2.5 100.0 3.0 0.0

-   -   RT min: 0.408, wavelength: 220 nm.

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrazin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.16 g, 0.369 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.05g, 0.369 mmol, 1 eq), EDCI.HCl (0.07 g, 0.369 mmol, 1 eq), HOBT (0.05 g,0.369 mmol, 1.0 eq) and TEA (0.15 ml, 1.107 mmol, 3 eq) were dissolvedin dichloromethane and the above mixture was stirred at room temperaturefor 18 h. The mixture was then added with water, and organic layerseparated and washed with water. The organic layer was dried over Na₂SO₄and concentrated. The crude product obtained was purified by Prep. HPLC.¹H NMR (400 MHz, CD₃OD): δ 1.43-1.46 (m, 2H), 1.72-1.75 (m, 2H), 2.37(s, 3H), 2.95 (s, 3H), 4.08 (s, 3H), 7.161 (s, 1H), 7.25-7.30 (m, 2H),7.35 (dd, J=2, 8.4 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.64 (d, J=8.4 Hz,1H), 7.76 (s, 1H), 7.96-7.99 (m, 2H), 8.36 (d, J=2.8 Hz, 1H),8.520-8.531 (m, 1H), 8.72 (d, J=1.2 Hz, 1H). LCMS: (ES+) m/z=551.2(M+H)⁺

Column: ZORBAX SB C18 (4.6×50)mm, 5 μm.

-   -   Mphase A: 10% CH₃OH-90% H₂O-0.1% TFA    -   Mphase B: 90% CH₃OH-10% H₂O-0.1% TFA    -   Flow: 5 ml/Min

Time % B 0.0 0.0 2.0 100.0 3.0 0.0

-   -   RT min: 2.039, wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150) mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 18.267    -   Wavelength: 220 nm, RT min: 18.267    -   Purity: 98.9%

HPLC COLUMN: XBridege phenyl (4.6×150) mm, 3.5 micron

-   -   Mobile Phase A: 0.05% TFA in Water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:Water (95:5) pH: 2.5    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.461    -   Wavelength: 220 nm, RT min: 16.461    -   Purity: 99.6%

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrazin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.149 g, 0.369 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.05g, 0.369 mmol, 1 eq), EDCI.HCl (0.07 g, 0.369 mmol, 1 eq), HOBT (0.05 g,0.369 mmol, 1.0 eq) and TEA (0.15 ml, 1.107 mmol, 3 eq) were dissolvedin dichloromethane and the above mixture was stirred at room temperaturefor 18 h. The mixture was then added with water, and organic layerseparated and washed with water. The organic layer was dried over Na₂SO₄and concentrated. The crude product obtained was purified by Prep. HPLC.¹H NMR (400 MHz, CD₃OD): δ 1.43-1.46 (m, 2H), 1.71-1.74 (m, 2H), 2.37(s, 3H), 2.95 (s, 3H), 7.25-7.31 (m, 2H), 7.40 (dd, J=2, 8.4 Hz, 1H),7.47 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.84-7.87(m, 2H), 7.95-8.00 (m, 2H), 8.37 (d, J=2.4 Hz, 1H), 8.52 (t, 1H), 8.59(s, 1H). LCMS: (ES+) m/z=521.2 (M+H)+

Column: Ascentis Express C18 (5×2.1)mm, 2.7 μm.

-   -   Mphase A: 2% Acetonitrile-98% Water-10 mM NH₄COOH    -   Mphase B: 98% Acetonitrile-2% Water-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0.0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.902, wavelength: 220 nm

HPLC COLUMN: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.807    -   Wavelength: 220 nm, RT min: 10.807    -   Purity: 99.1%

HPLC COLUMN: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.897    -   Wavelength: 220 nm, RT min: 9.897    -   Purity: 99.7%

Preparative HPLC Method

Column: Xbridge C18 (19×100) mm, 5μ

-   -   Mobile phase: 0.1% TFA in water (A), MeCN (B)    -   Flow: 12 ml/min    -   Gradient:

Time % B 0 30 10 45

-   -   RT=18 min.

4-methylpyrimidine-2-carbonitrile

A mixture of 2-chloro-4-methylpyrimidine (725 mg, 5.63 mmol, 1 eq),zinccyanide (396 mg, 3.38 mmol, 0.6 eq) andtetrakis(triphenylphosphine)palladium(0) (716 mg, 0.562, 0.1 eq) in DMF(10 ml) was heated at 110° C. under nitrogen for 1 hr. The mixture wascooled to r.t., diluted with EtOAc and washed twice with 2N ammoniumhydroxide (50 ml). The organic layer was washed with brine (20 ml) driedover sodium sulphate and concentrated in vacuum to provide the crudemixture. The crude product was then purified by column chromatography(30% EtOAc in Hexane) to afford 4-methylpyrimidine-2-carbonitrile Yield:380 mg (56%). ¹H NMR (400 MHz, CDCl₃): δ 2.61 (s, 3H), 7.36 (d, 1H,J=5.2 Hz), 8.66 (d, 1H, J=5.2 Hz),1-(4-methylpyrimidin-2-yl)cyclopropanamine. To a solution of4-methylpyrimidine-2-carbonitrile (200 mg, 1.7 mmol, 1 eq) in dry THFunder an argon atmosphere was added titanium isopropoxide (0.58 ml, 2.0mmol, 1.2 eq) slowly at ambient temperature and the reaction mixture wasstirred for 15 min. Ethyl magnesium bromide (1 M solution) in THF (4 ml,4.0 mmol, 2.4 eq) was added via syringe slowly at ambient temperature(during the addition of EtMgBr, the reaction mixture turned black). Thenthe reaction mixture was stirred for an hour. BF₃.EtO (0.36 ml, 2.6mmol, 1.5 eq) was added slowly through syringe to the mixture at 0° C.The mixture was allowed to attain ambient temperature and stirred foranother one hour. 10 ml of water was added to the reaction mixture,which was then filtered through Celite and the bed washed with water andethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9)and then extracted with DCM. The organic was washed with brine, driedover sodium sulphate and concentrated to get the crude product which wastaken for coupling reaction without further purification. Yield: 120 mg(crude).

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(4-methylpyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.099 mmol, 1 eq),1-(4-methylpyrimidin-2-yl)cyclopropanamine (120 mg, crude), Py-Bop(0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 31 mg (58%). ¹H NMR (400 MHz, CD₃OD): δ 8.48 (d, J=5.0 Hz, 1H),8.02-7.95 (m, 2H), 7.89-7.82 (m, 2H), 7.67 (d, J=5.8 Hz, 2H), 7.48-7.37(m, 2H), 7.33-7.23 (m, 2H), 7.19-7.13 (m, 1H), 2.96 (s, 3H), 2.48 (s,3H), 2.36 (s, 3H), 1.82-1.75 (m, 2H), 1.51-1.43 (m, 2H) LCMS: (ES+)m/z=535.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.94, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.02    -   Wavelength: 220 nm, RT min: 11.02

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.22    -   Wavelength: 220 nm, RT min: 10.22

5-methylpyrimidine-2-carbonitrile

To a 10 ml microwave vial was charged with 2-chloro-5-methylpyrimidine(0.97 g, 7.54 mmol, 1 eq), Pd₂(dba)₃ (0.274 g, 0.3 mmol, 0.04 eq), DPPF(0.335 g, 0.6 mmol, 0.08 eq), zinc cyanide (0.575 g, 4.9 mmol, 0.65 eq),and zinc dust (0.118 g, 1.81 mmol, 0.24 eq). The flask was evacuated andbackfilled with N₂ and anhydrous dimethylacetamide. The vial was mountedonto a microwave reactor and heated at 100° C. for 10 hr. The reactionmixture was diluted with EtOAc and then washed with brine thrice, driedover sodium sulphate and concentrated in vacuum to provide the crudemixture. The crude was then purified by column chromatography (30% EtOAcin Hexane) to afford 5-fluoro pyrimidine-2-carbonitrile Yield: 458 mg(51%). ¹H NMR (400 MHz, CDCl₃): δ 2.43 (s, 3H), 8.67 (s, 2H).

1-(5-methylpyrimidin-2-yl)cyclopropanamine

To a solution of 5-methylpyrimidine-2-carbonitrile (200 mg, 1.7 mmol, 1eq) in dry THF under an argon atmosphere was added titanium isopropoxide(0.58 ml, 2.0 mmol, 1.2 eq) slowly at ambient temperature and thereaction mixture was stirred for 15 mins Ethyl magnesium bromide (1Msolution) in THF (4 ml, 4.0 mmol, 2.4 eq) was added via syringe slowlyat ambient temperature. Then the reaction mixture was stirred for anhour. BF₃.EtO (0.36 ml, 2.6 mmol, 1.5 eq) was added slowly throughsyringe to the mixture at 0° C. The mixture was allowed to attainambient temperature and stirred for another one hour. 10 ml of water wasadded to the reaction mixture which was then filtered through Celite andthe bed washed with water and ethyl acetate. The filtrate was basifiedwith 10% NaOH solution (pH=9) then extracted with DCM. The organic waswashed with brine solution, dried over sodium sulphate and concentratedto give the crude product which was taken for coupling reaction withoutfurther purification. Yield: 125 mg (crude).

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methylpyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.099 mmol, 1 eq),1-(5-methylpyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop(0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative TLC(Eluent Chloroform:Methanol 9.5:0.5, 200 ml). Yield: 29 mg (54%). ¹H NMR(400 MHz, CD₃OD): δ 8.50 (d, J=0.5 Hz, 2H), 8.03-7.94 (m, 2H), 7.89-7.82(m, 2H), 7.69-7.64 (m, 2H), 7.47-7.37 (m, 2H), 7.33-7.24 (m, 2H), 2.96(s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 1.77-1.70 (m, 2H), 1.47-1.40 (m,2H) LCMS: (ES+) m/z=535.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.93, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 6 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.02    -   Wavelength: 220 nm, RT min: 11.02

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.19    -   Wavelength: 220 nm, RT min: 10.19

5-fluoropyrimidine-2-carbonitrile

To a 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine(1.0 g, 7.54 mmol, 1 eq), Pd₂(dda)₃ (0.274 g, 0.3 mmol, 0.04 eq), DPPF(0.335 g, 0.6 mmol, 0.08 eq), zinc cyanide (0.575 g, 4.9 mmol, 0.65 eq),and zinc dust (0.118 g, 1.81 mmol, 0.24 eq). The flask was evacuated andbackfilled with N₂ and anhydrous dimethylacetamide. The vial was mountedonto a microwave reactor and heated at 100° C. for 10 hr. The reactionmixture was diluted with EtOAc and then washed with brine thrice, driedover sodium sulphate and concentrated in vacuum to provide the crudemixture. The crude was then purified by column chromatography (30% EtOAcin Hexane) to afford 5-fluoropyrimidine-2-carbonitrile Yield: 468 mg(51%). ¹H NMR (400 MHz, CDCl₃): δ 8.73 (s, 2H).

1-(5-fluoropyrimidin-2-yl)cyclopropanamine

To a solution of 5-fluoropyrimidine-2-carbonitrile (200 mg, 1.6 mmol, 1eq) in a dry THF under an argon atmosphere was added titaniumisopropoxide (0.55 ml, 1.9 mmol, 1.2 eq) at ambient temperature and thereaction mixture was stirred for 15 min. Ethyl magnesium bromide (1Msolution) in THF (4 ml, 4.0 mmol, 2.5 eq) was added via syringe slowlyat ambient temperature. Then the reaction mixture was stirred for anhour. BF₃.EtO (0.34 ml, 2.4 mmol, 1.5 eq) was added slowly throughsyringe to the mixture at 0° C. The mixture was allowed to attainambient temperature and stirred for another one hour. 10 ml of water wasadded to the reaction mixture which was then filtered through Celite andthe bed washed with water and ethyl acetate. The filtrate was basifiedwith 10% NaOH solution (pH=9) then extracted with DCM and washed withbrine solution, dried over sodium sulphate and concentrated to give thecrude product which was taken for coupling reaction without furtherpurification. Yield: 125 mg (crude).

2-(4-Fluorophenyl)-5-(5-(1-(5-fluoropyrimidin-2-yl)-cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.099 mmol, 1 eq),1-(5-fluoropyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop(0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative TLC(Eluent Chloroform:Methanol 9.5:0.5 200 ml. Yield: 32 mg (55%). ¹H NMR(400 MHz, CD₃OD): δ 8.58 (d, J=0.5 Hz, 2H), 8.05-7.93 (m, 2H), 7.89-7.79(m, 2H), 7.68 (s, 2H), 7.49-7.36 (m, 2H), 7.34-7.23 (m, 2H), 2.96 (s,3H), 2.36 (s, 3H), 1.83-1.68 (m, 2H), 1.55-1.38 (m, 2H). LCMS: (ES+)m/z=539.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.97, wavelength: 220 nm

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.53    -   Wavelength: 220 nm, RT min: 10.53

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(4-methyl-pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.092 mmol, 1 eq),1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop(0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 0.028 g (53%). ¹H NMR (400 MHz, CD₃OD): δ 8.49 (d, J=5.3 Hz, 1H),8.07-7.95 (m, 2H), 7.92 (s, 1H), 7.69-7.51 (m, 2H), 7.39-7.23 (m, 3H),7.16 (d, J=5.3 Hz, 2H), 4.08 (s, 3H), 2.95 (s, 3 H), 2.49 (s, 3H), 2.37(s, 3H), 1.87-1.76 (m, 2H), 1.57-1.45 (m, 2H). ¹⁹F NMR (376.47 MHz,CD₃OD): δ −78.09 (TFA), −113.44 LCMS: (ES+) m/z=565.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.98, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 7 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.37    -   Wavelength: 220 nm, RT min: 11.37

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.53    -   Wavelength: 220 nm, RT min: 10.53

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyl-pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.092 mmol, 1 eq),1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop(0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 0.025 g (49%). ¹H NMR (400 MHz, CD₃OD): δ 8.50 (d, J=0.8 Hz, 2H),8.01-7.96 (m, 2H), 7.92 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.3Hz, 1H), 7.34 (dd, J=1.9, 8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (s, 1H),4.08 (s, 3H), 2.96 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 1.80-1.69 (m,2H), 1.52-1.43 (m, 2H). ¹⁹F NMR (376.47 MHz, CD₃OD): 6-113.45 LCMS:(ES+) m/z=565.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.97, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 8 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.50    -   Wavelength: 220 nm, RT min: 11.50

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.57    -   Wavelength: 220 nm, RT min: 10.57

2-(4-Fluorophenyl)-5-(5-(1-(5-fluoropyrimidin-2-yl)cyclo-propylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.092 mmol, 1 eq),1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop(0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 0.03 g (57%). ¹H NMR (400 MHz, CD₃OD): δ 8.59 (s, 2H), 8.04-7.93(m, 2H), 7.90 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.34 (dd,J=1.8, 8.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.15 (s, 1 H), 4.07 (s, 3H),3.00-2.92 (m, 3H), 2.37 (s, 3H), 1.80-1.72 (m, 2H), 1.54-1.43 (m, 2H).¹⁹F NMR (376.47 MHz, CD₃OD): δ −113.44, 146.33 LCMS: (ES+) m/z=569.2(M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.99, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 9 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.91    -   Wavelength: 220 nm, RT min: 11.91

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.95    -   Wavelength: 220 nm, RT min: 10.95

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(4-methylpyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.089 mmol, 1 eq),1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen wasadded triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic layer wasfurther washed with water, dried over sodium sulphate and concentrated.The product obtained was purified by preparative HPLC. Yield: 0.022 g(42%). ¹H NMR (400 MHz, CD₃OD): δ 8.54 (d, J=5.6 Hz, 1H), 7.97-7.94 (m,2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 4H), 7.19 (s,1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 1.89-1.86(m, 2H), 1.59-1.56 (m, 2H). ¹⁹F NMR (376.57 MHz, CD₃OD): δ −77.65 (TFA),−112.33, −122.77 LCMS: (ES+) m/z=583.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.96, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 10 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.27    -   Wavelength: 220 nm, RT min: 11.27

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.51    -   Wavelength: 220 nm, RT min: 10.51

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methylpyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.089 mmol, 1 eq),1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen wasadded triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic layer wasfurther washed with water, dried over sodium sulphate and concentrated.The product obtained was purified by preparative HPLC. Yield: 0.025 g(48%). ¹H NMR (400 MHz, CD₃OD): δ 8.58 (d, J=0.8 Hz, 2H), 7.97-7.94 (m,2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s,1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.82-1.79(m, 2H), 1.55-1.52 (m, 2H). ¹⁹F NMR (376.57 MHz, CD₃OD) δ −77.67 (TFA),−112.34, −122.75 LCMS: (ES+) m/z=583.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.95, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 11 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.23    -   Wavelength: 220 nm, RT min: 11.23

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.46    -   Wavelength: 220 nm, RT min: 10.46

4-Fluoro-2-(4-fluorophenyl)-5-(5-(1-(5-fluoropyrimidin-2-yl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.089 mmol, 1 eq),1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen wasadded triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture wasstirred at ambient temperature for 12 h. The mixture was concentrated,diluted with water and extracted with EtOAc. The organic layer wasfurther washed with water, dried over sodium sulphate and concentrated.The product obtained was purified by preparative HPLC. Yield: 0.023 g(44%). ¹H NMR (400 MHz, CD₃OD): δ 8.59 (d, J=0.4 Hz, 2H), 7.98-7.94 (m,2H), 7.87 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.18 (s,1H), 4.09 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.79-1.76 (m, 2H),1.52-1.48 (m, 2H). ¹⁹F NMR (376.57 MHz, CD₃OD) δ −77.62 (TFA), −112.36,−122.73, −145.58 LCMS: (ES+) m/z=587.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.97, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 12 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 11.51    -   Wavelength: 220 nm, RT min: 11.51

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.79    -   Wavelength: 220 nm, RT min: 10.79

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(4-methylpyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.095 mmol, 1 eq),1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop(0.064 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature undernitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 0.024 g (46%). ¹H NMR (400 MHz, CDCl₃): δ 8.63 (d, J=6.0 Hz, 1H),8.39 (bs, 1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d,J=1.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.34 (d, J=5.6 Hz, 1H), 7.21-7.15 (m,3H), 6.39 (bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.71 (s, 3H), 2.24 (s, 3 H),2.06-2.03 (m, 2H), 1.74-1.71 (m, 2H). ¹⁹F NMR (376.47 MHz, CDCl₃) δ−75.92 (TFA), −109.79, −119.33. LCMS: (ES+) m/z=553.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.92, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 13 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.59    -   Wavelength: 220 nm, RT min: 10.59

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.98    -   Wavelength: 220 nm, RT min: 9.98

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(5-methylpyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.095 mmol, 1 eq),1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop(0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature undernitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 0.023 g (44%). ¹H NMR (400 MHz, CDCl₃): δ 8.64 (s, 2H), 8.14 (bs,1H), 7.99-7.95 (m, 2H), 7.82 (dd, J=2.0, 8.0 Hz, 1H), 7.66 (bs, 1H),7.42 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.21-7.15 (m, 3 H), 6.18(bs, 1H), 3.03 (d, J=4.8 Hz, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.92 (m,2H), 1.67 (m, 2H). ¹⁹F NMR (376.47 MHz, CDCl₃) δ −76.71 (TFA), −110.50,−120.06. LCMS: (ES+) m/z=553.2 (M+H)+

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.90, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 14 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 17.19    -   Wavelength: 220 nm, RT min: 17.19

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 15.84    -   Wavelength: 220 nm, RT min: 15.84

4-Fluoro-2-(4-fluorophenyl)-5-(5-(1-(5-fluoropyrimidin-2-yl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.095 mmol, 1 eq),1-(5-fluoropyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop(0.064 g, 0.12 mmol, 1.3 eq), in DMF at ambient temperature undernitrogen was added triethylamine (0.029 g, 0.28 mmol, 3 eq). The clearmixture was stirred at ambient temperature for 12 h. The mixture wasconcentrated, diluted with water and extracted with EtOAc. The organiclayer was further washed with water, dried over sodium sulphate andconcentrated. The product obtained was purified by preparative HPLC.Yield: 0.026 g (50%). ¹H NMR (400 MHz, CDCl₃): δ 8.46 (s, 2H), 7.99-7.95(m, 2H), 7.80 (dd, J=2.0, 8.0 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.43-7.39(m, 2H), 7.23-7.15 (m, 3H), 7.07 (bs, 1H), 6.18 (bs, 1H), 3.03 (d, J=4.8Hz, 3H), 2.27 (s, 3H), 1.81-1.78 (m, 2H), 1.55-1.53 (m, 2H). ¹⁹F NMR(376.47 MHz, CDCl₃) δ −75.77 (TFA), −109.62, −119.26, −142.84 LCMS:(ES+) m/z=557.4 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.92, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 15 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.98    -   Wavelength: 220 nm, RT min: 10.98

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.33    -   Wavelength: 220 nm, RT min: 10.33

1-(furan-2-yl)cyclopropanamine

To a solution of 2-furonitrile (5 g, 53.71 mmol, 1.0 eq) in dry THFunder an argon atmosphere was added slowly titanium isopropoxide (18.9ml, 64.4 mmol, 1.2 eq) at r.t. The reaction mixture was stirred for 15min. A 1M solution of EtMgBr in THF (129 ml, 129 mmol, 2.4 eq) was addedslowly via syringe to the mixture at 0° C. After addition, the reactionmixture was allowed to warm to r.t. and stirred at r.t. for 2 hour.BF₃.Et₂O (10.4 ml) was then added slowly to the mixture at 0° C. Afterthe completion of addition, the reaction mixture was stirred at r.t. for30 min. The reaction mixture was added with ice, and then with 10% NaOHsolution slowly till the reaction mixture becomes basic. The mixture wasextracted with EtOAc. The organic was washed with brine, dried overNa₂SO₄ and concentrated. The crude product was purified by silica gel(60-120) column chromatography using 35% EtOAc/Pet ether as eluent.Yield: 2.5 g (crude).

tert-butyl 1-(furan-2-yl)cyclopropylcarbamate

A solution of 1-(furan-2-yl)cyclopropanamine (2.3 g, 18.69 mmol, 1.0 eq)in THF (25 ml) was added Boc anhydride (4.9 g, 22.47 mmol, 1.2 eq) at 0°C. and then stirred at r.t. overnight. The reaction mixture wasconcentrated and crude product was purified by silica gel (60-120)column chromatography using 5% EtOAc/Pet ether as eluent. Yield: 2.5 g(60%). ¹H NMR (400 MHz, CDCl₃): δ 1.17 (s, 2H), 1.28 (s, 2H), 1.43 (s,9H), 5.21 (bs, 1H) 6.09 (d, J=2.8 Hz, 1H), 6.26 (q, J=3.2 Hz 1H), 7.23(q, J=2.0 Hz, 1H). LCMS (ES+) m/z=123.7 (M)⁺

tert-butyl 1-(pyridazin-3-yl)cyclopropylcarbamate

A solution of tert-butyl 1-(furan-2-yl)cyclopropylcarbamate (2.15 g,9.64 mmol, 1.0 eq) in acetone (86 ml) and water (86 ml) was purged N₂and cooled to −20° C. NaHCO₃ (1.62 g, 19.28 mmol, 2.0 eq) andN-bromosuccinimide (2.23 g, 12.52 mmol, 1.3 eq) were added to themixture at −20° C. which was stirred at the same temperature for 2 hr.To the reaction mixture at −20° C. was added THF (4.3 ml) and thetemperature raised to 0° C. over 30 min. Acetone was removed from thereaction mixture by a stream of N₂ and to the residue at 0° C. was addedisopropanol (86 ml) followed by hydrazine hydrate (12.9 ml). Thereaction mixture was stirred at r.t. overnight. Product formation wasconfirmed by LCMS. After removal of the solvent by vacuum, the residuewas diluted with water and extracted with EtOAc. The organic was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel (60-120) column chromatography using4% MeOH/CHCl₃ as eluent. Yield: 0.8 g (36%). ¹H NMR (400 MHz, CDCl₃): δ8.95 (d, J=3.6 Hz, 1H), 7.53 (d, J=8 Hz, 1H), 7.39 (m, 1H), 5.45 (bs,1H), 1.82 (m, 2H), 1.46 (s, 9H) 1.24 (m, 2H). LCMS: (ES+) m/z=236.2(M+H)⁺

1-(pyridazin-3-yl)cyclopropanamine hydrochloride

To a solution of tert-butyl 1-(pyridazin-3-yl)cyclopropylcarbamate (0.3g) in THF (3 ml) at 0° C. was added HCl in dioxane (5 ml) and themixture stirred at r.t. for 3 hr. The reaction mixture was concentrated,and the crude product was taken for the next coupling reaction. Yield:0.21 g

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridazin-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.092 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HClsalt (0.017 g, 0.092 mmol, 1 eq) and Py-Bop (0.062 g, 0.12 mmol, 1.3 eq)in DMF at ambient temperature under nitrogen was added triethylamine(0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambienttemperature for 12 h. The mixture was concentrated, diluted with waterand extracted with EtOAc. The organic layer was further washed withwater, dried over sodium sulphate and concentrated. The product obtainedwas purified by flash column chromatography using 4% MeOH/CHCl₃ aseluant. Yield: 0.032 g (63%). ¹H NMR (400 MHz, CD₃OD): δ 9.15 (s, 1H),9.00 (d, J=3.8 Hz, 1H), 8.53-8.40 (m, 1H), 8.02-7.95 (m, 2H), 7.84 (dd,J=1.5, 8.5 Hz, 1H), 7.79 (s, 1H), 7.70-7.62 (m, 2H), 7.59 (d, J=1.5 Hz,1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.31-7.26 (m, 2H), 7.16 (s, 1H), 4.09(s, 3H), 2.98-2.95 (m, 3H), 2.38 (s, 3H), 1.89-1.87 (m, 2H), 1.57-1.52(m, 2H). ¹⁹F NMR (376.57 MHz, CD₃OD): δ −112.66 LCMS: (ES+) m/z=551.2(M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.88, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 16 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.35    -   Wavelength: 220 nm, RT min: 10.35

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.77    -   Wavelength: 220 nm, RT min: 9.77

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridazin-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.099 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HClsalt (0.018, 0.099 mmol, 1 eq) and Py-Bop (0.067 g, 0.13 mmol, 1.3 eq)in DMF at ambient temperature under nitrogen was added triethylamine(0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambienttemperature for 12 h. The mixture was concentrated, diluted with waterand extracted with EtOAc. The organic layer was further washed withwater, dried over sodium sulphate and concentrated. The product obtainedwas purified by preparative HPLC. Yield: 0.031 mg (60%). ¹H NMR (400MHz, CDCl₃): δ 9.17 (s, 1H), 7.92-7.96 (m, 3H), 7.77-7.69 (m, 4H), 7.65(s, 1 H), 7.56 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (dd,J=1.6, 8.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.94 (bs, 1H), 3.0 (s, 3H), 2.33(s, 3H), 1.89-1.86 (m, 2H), 1.60-1.57 (m, 2H). ¹⁹F NMR (376.47 MHz,CDCl₃): δ −75.82 (TFA), −109.29 LCMS: (ES+) m/z=521.0 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.86, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 17 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.77    -   Wavelength: 220 nm, RT min: 9.77

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.33    -   Wavelength: 220 nm, RT min: 9.33

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridazin-3-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.095 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HClsalt (0.017, 0.095 mmol, 1 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq)in DMF at ambient temperature under nitrogen was added triethylamine(0.029 g, 0.28 mmol, 3 eq). The clear mixture was stirred at ambienttemperature for 12 h. The mixture was concentrated, diluted with waterand extracted with EtOAc. The organic layer was further washed withwater, dried over sodium sulphate and concentrated. The product obtainedwas purified by preparative HPLC. Yield: 0.029 g (57%). ¹H NMR (400 MHz,CD₃OD): δ 9.14 (d, J=3.6 Hz, 1H), 7.97-7.85 (m, 6H), 7.56 (d, J=8.4 Hz,1H), 7.51 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s,3H), 1.89-1.86 (m, 2H), 1.62-1.59 (m, 2H). ¹⁹F NMR (376.57 MHz, CD₃OD):δ −77.63 (TFA), −112.22, −112.77 LCMS: (ES+) m/z=539.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.83, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 18 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.49    -   Wavelength: 220 nm, RT min: 9.49

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.28    -   Wavelength: 220 nm, RT min: 9.28

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridazin-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.089 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HClsalt (0.017 g, 0.089 mmol, 1 eq) and Py-Bop (0.06 g, 0.11 mmol, 1.3 eq)in DMF at ambient temperature under nitrogen was added triethylamine(0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambienttemperature for 12 h. The mixture was concentrated, diluted with waterand extracted with EtOAc. The organic layer was further washed withwater, dried over sodium sulphate and concentrated. The product obtainedwas purified by flash column chromatography using 4% MeOH/CHCl₃ aseluant. Yield: 0.033 g (63%). ¹H NMR (400 MHz, CD₃OD): δ 9.15 (s, 1H),8.98 (d, 1H), 8.75 (d, J=4.0 Hz, 1H), 7.97-7.93 (m, 2H), 7.82 (dd,J=1.6, 8.8 Hz, 1H), 7.76 (s, 1H), 7.66 (dd, J=5.2, 8.8 Hz, 1H), 7.52 (d,J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.09 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.88 (m, 2H), 1.54 (m, 2H). LCMS: (ES+) m/z=569.2(M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.89, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150) mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 19 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 15.49    -   Wavelength: 220 nm, RT min: 15.49

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 15.10    -   Wavelength: 220 nm, RT min: 15.10

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrazin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.04 g, 0.095 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.015g, 0.011 mmol, 1.2 eq) and Py-Bop (0.064 g, 0.12 mmol, 1.3 eq) in DMF atambient temperature under nitrogen was added triethylamine (0.029 g,0.28 mmol, 3 eq). The clear mixture was stirred at ambient temperaturefor 12 h. The mixture was concentrated, diluted with water and extractedwith EtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was purified bypreparative HPLC. Yield: 0.034 g (66%). ¹H NMR (400 MHz, CD₃OD): δ 8.60(d, J=1.6 Hz, 1H), 8.52 (m, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.98-7.95 (m,2H), 7.92 (dd, J=1.6, 7.8 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.55 (d,J=8.4 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.36-7.28 (m, 3H), 2.96 (s, 3H),2.30 (s, 3H), 1.73-1.71 (m, 2H), 1.47-1.43 (m, 2H). ¹⁹F NMR (376.57 MHz,CD₃OD) 6-77.68 (TFA), −112.27, −122.72 LCMS: (ES+) m/z=539.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.87, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 20 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.40    -   Wavelength: 220 nm, RT min: 10.40

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.83    -   Wavelength: 220 nm, RT min: 9.83

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrazin-2-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.04 g, 0.089 mmol, 1 eq), 1-(pyrazin-2-yl)cyclopropanamine (0.014g, 0.01 mmol, 1.2 eq) and Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF atambient temperature under nitrogen was added triethylamine (0.027 g,0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperaturefor 12 h. The mixture was concentrated, diluted with water and extractedwith EtOAc. The organic layer was further washed with water, dried oversodium sulphate and concentrated. The product obtained was purified bypreparative HPLC. Yield: 0.031 g (62%). ¹H NMR (400 MHz, CD₃OD): δ 8.73(br. s., 1H), 8.56 (br. s., 1H), 8.47-8.31 (m, 1H), 8.06-7.88 (m, 2H),7.74 (s, 1H), 7.53 (s, 1H), 7.36-7.26 (m, 3H), 7.19 (s, 1H), 4.10 (s,3H), 2.96 (s, 3H), 2.31 (s, 3H), 1.84-1.67 (m, 2H), 1.56-1.38 (m, 2H).¹⁹F NMR (376.57 MHz, CD₃OD) δ −77.80 (TFA), −112.34, −122.74 LCMS: (ES+)m/z=569.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ml/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.91, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 21 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.91    -   Wavelength: 220 nm, RT min: 10.91

HPLC Method: XBridege phenyl (4.6×150) mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   Flow: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.17    -   Wavelength: 220 nm, RT min: 10.17

2-Chloro-4,6-dimethylpyrimidine

To a 50 ml single neck round-bottomed flask was added4,6-dimethylpyrimidin-2-ol (5.0 g, 0.04 mol) followed by POCl₃ (15.0 ml,0.097 mol). The resulting suspension was heated to reflux overnight.Heating was stopped. After cooling, the mixture was concentrated, pouredinto crushed ice and extracted with diethyl ether (100 ml×2). Theorganic layer was washed with 10% NaHCO₃ solution, dried over Na₂SO₄ andevaporated to get a pale yellow solid. Yield: 3.3 g (58%) ¹H NMR (400MHz, CDCl₃): δ 2.48 (s, 6H), 6.97 (s, 1H). LCMS: (ES+) m/z=143.6 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.428, wavelength: 220 nm

4,6-dimethylpyrimidine-2-carbonitrile

2-Chloro-4,6-dimethylpyrimidine (3.3 g, 0.023 mol) was combined withzinc cyanide (2.7 g, 0.023 mol, 1 eq.) andtetrakis(triphenylphosphine)palladium (0) (2.7 g, 0.0023 mol, 0.1 eq.)in DMF (20 ml), and the slurry was heated at 110° C. under nitrogen for0.5 h. The mixture was cooled to room temperature, diluted with EtOAc(70 ml) and washed twice with 2N ammonium hydroxide (50 ml). The EtOAcsolution was washed with brine (20 ml) and concentrated in vacuum toprovide the crude mixture. The crude was then purified by columnchromatography (30% EtOAc/hexane) to afford4,6-dimethylpyrimidine-2-carbonitrile. Yield: 0.8 g (26%). ¹H NMR (400MHz, CDCl₃): δ 2.48 (s, 6H), 7.21 (s, 1H). LCMS: (ES+) m/z=133.6 (M)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.239, wavelength: 220 nm

1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine

To a stirred solution of 4,6-dimethylpyrimidine-2-carbonitrile (0.2 g,1.5 mmol) in anhydrous THF was added Ti(OiPr)₄ (0.43 ml, 1.8 mmol, 1.2eq.). After stirring for 15 min., Ethyl magnesium bromide (3.8 ml, 3.8mmol, 2.5 eq.) in THF was added dropwise to the mixture at −78° C.(during the addition of EtMgBr the reaction mixture turned black). Thereaction mixture was then stirred for an hour at room temperature, andthen BF₃.Et₂O (0.320 ml, 2.2 mmol, 1.5 eq.) was added slowly to themixture at 0° C. After the addition completed, the reaction was stirredat room temperature for one hour. 50 ml of water was added to thereaction mixture which was then filtered through Celite. The filtratewas basified with 10% NaOH solution (pH=9) and then extracted with DCM(25 ml×2) and washed with brine. The organic layer was concentrated toyield crude product was taken for the next step without purification.

5-(5-(1-(4,6-dimethylpyrimidin-2-yl)cyclopropycarbamoyl)-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (50 mg, 0.12 mmol), crude1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (150 mg) in 2 ml DMF atroom temperature was added BOP (106 mg, 0.24 mmol, 2.0 eq.) and triethylamine (0.050 ml, 0.36 mmol, 3.0 eq.), and the mixture stirred overnightunder an N₂ atmosphere. The mixture was poured into crushed ice, andsolid precipitate was filtered and dried. The product obtained wasfurther purified by column chromatography using Silica gel (230-400) andCHCl₃-MeOH (95:5) as a mobile phase. Yield: 40 mg (60%). ¹H NMR (400MHz, CDCl₃): δ 8.00-7.97 (m, 2H), 7.80-7.76 (m, 2H), 7.41-7.37 (m, 3H),7.21-7.15 (m, 3H), 6.77 (s, 1H), 6.22 (br. s., 1H), 3.01 (d, J=5.0 Hz,3H), 2.37 (s, 6H), 2.26 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.54 (m, 2H).¹⁹F NMR (376.57 MHz, CDCl₃): δ −109.83, −119.22 LCMS: (ES+) m/z=567.2(M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.971, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150) mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5 adjusted with dil NH₃    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 22 10 29 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.83    -   Wavelength: 220 nm, RT min: 16.83    -   Purity: 95.31%

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.03    -   Wavelength: 220 nm, RT min: 16.03    -   Purity: 96.63%

5-(5-(1-(4,6-dimethylpyrimidin-2-yl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-4-fluoro-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (50 mg, 0.11 mmol), crude1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (100 mg) in 2 ml DMF atroom temperature was added BOP (100 mg, 0.22 M, 2.0 eq.) and triethylamine (0.046 ml 0.33 M, 3.0 eq.), and the mixture stirred overnightunder an N₂ atmosphere. The mixture was poured into crushed ice, and thesolid precipitate was filtered and dried. The product obtained wasfurther purified by preparative HPLC. Yield: 15 mg (24%) ¹H NMR (400MHz, CD₃OD): δ 7.97-7.94 (m, 2H), 7.89 (s, 1H), 7.51 (d, J=8.5 Hz, 1H),7.31-7.25 (m, 3H), 7.19 (s, 1H), 7.14 (s, 1H), 4.11 (s, 3H), 2.96 (s,3H), 2.48 (s, 6H), 2.31 (s, 3H), 1.86-1.83 (m, 2H), 1.55-1.52 (m, 2H).¹⁹F NMR (376.57 MHz, CD₃OD) δ −77.40 (TFA), −112.33, −122.75 (CFCl₃ asreference). LCMS: (ES+) m/z=597.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 2.01, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5 adjusted with dil NH₃    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 23 10 30 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.97    -   Wavelength: 220 nm, RT min: 17.97    -   Purity: 98.65%

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.61    -   Wavelength: 220 nm, RT min: 16.61    -   Purity: 98.78%

Preparative HPLC Method:

Column: X-bridge C18 (100×4.6×5.0μ)

-   -   Mobile Phase A: 0.05% TFA in Water    -   Mobile Phase B: Acetonitrile    -   Gradient:

Time Flow A(%) B(%) 0 15 ml/min 80 20 5 15 ml/min 55 45

-   -   RT: 18 min.

tert-butyl 1(methoxy(methyl)carbamoyl)cyclopropylcarbamate

To a solution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid(11.00 g, 54.7 mmol, 1.0 eq) in methylene chloride at 0° C. was addedN,O-dimethyl hydroxylamine HCl (5.9 g, 60.4 mmol, 1.1 eq), TEA (13.82 g,13.6 mmol, 2.5 eq) and HATU (22.90 g, 60.2 mmol, 1.1 eq). The resultingreaction mixture was stirred at room temperature under an N₂ atmosphereovernight. After TLC showed reaction was completed, the reaction mixturewas concentrated, diluted with water and extracted with diethyl ether.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to get the desired product as a white solid. Yield: 13.00 g(97.52%).

tert-butyl 1-propioloylcyclopropylcarbamate

To a stirred solution of tert-butyl1-(methoxy(methyl)carbamoyl)cyclopropylcarbamate (5.0 g, 20.49 mmol, 1.0eq) in THF at −78° C. was added (trimethylsilyl)acetylene (6.36 g, 61.15mmol, 3.0 eq), and the stirring continued at the same temperature for 5hr. Product formation was confirmed by LCMS. Saturated NH₄Cl solutionwas added to the reaction mixture, which was then extracted with EtOAC.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by column chromatographyusing silica gel (60-120). The desired compound was eluted with 15%EtOAC in Pet ether. Yield: 1.5 g (35.70%).

(E)-tert-butyl 1-(3-(dimethylamino)acryloyl)cyclopropylcarbamate

A 2M solution of dimethylamine in THF (14.5 ml) and tert-butylpropioloylcyclopropylcarbamate (1.5 g, 7.17 mmol, 1.0 eq) was stirred at0° C., and then the stirring continued at r.t. for 4 hr. TLC showedcompletion of the reaction. The reaction mixture was concentrated toyield the crude solid product which was then recrystalised in EtOAC/Petether to get the desired product as light yellow solid. Yield: 1.4 g(77.8%). ¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, J=12.4, 1H), 5.52 (d,J=10.8, 1H), 5.37 (d, J=12.4, 1H), 3.07 (bs, 3H), 2.82 (bs, 3H), 1.52(s, 2H), 1.45 (s, 9H), 1.05 (s, 2H). LCMS: (ES+) m/z=255.2 (M+H)⁺

Column: Ascentis Express C8 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.57, wavelength: 220 nm

tert-butyl 1-(pyrimidin-4-yl)cyclopropylcarbamate

A solution of (E)-tert-butyl 1-(3-(dimethylamino)acryloyl)cyclopropylcarbamate (0.300 g, 1.18 mmol, 1.0 eq), formamidine acetate (0.490 g,4.724 mmol, 4.0 eq) and sodium methoxide (0.510 g, 9.44 mmol, 8.0 eq) inMeOH in a pressure tube was stirred at 90° C. overnight. TLC and LCMSshowed completion of the reaction. The reaction mixture was diluted withwater, extracted with EtOAC. The organic was washed with brine, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby silica gel (60-120) column chromatography using 30% EtOAC/hexane aseluent. Yield: 0.180 g (65.0%). ¹H NMR (400 MHz, CDCl₃): δ 9.0 (s, 1H),8.58 (d, J=5.6, 1H), 7.37 (d, J=4.0, 1H), 5.27 (bs, 1H), 1.73 (s, 2H),1.48 (s, 9H), 1.36 (s, 2H). LCMS: (ES+) m/z=236.2 (M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm)

-   -   Mphase A: 20 mM NH₄OAC IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAC IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100.0 0.0

-   -   RT min: 1.33, wavelength: 220 nm

1-(pyrimidin-4-yl)cyclopropanamine HCl salt

A solution of tert-butyl 1-(pyrimidin-4-yl)cyclopropylcarbamate (0.100g, 0.425 mmol, 1.0 eq), in 4.0 M HCl in 1,4-dioxane (4.0 ml) was stirredat r.t. for 5 hr. The reaction mixture was concentrated completely andthe HCl salt was taken to next step.

1-(furan-3-yl)cyclopropanamine

To solution of 3-furonitrile (5 g, 53.71 mmol, 1.0 eq) in dry THF atr.t. under an argon atmosphere was added slowly titanium isopropoxide(18.9 ml, 64.4 mmol, 1.2 eq). The reaction mixture was stirred for 15min. A solution of 1.0 M ethyl magnesium bromide in THF (129 ml, 128mmol, 2.4 eq) was added via syringe slowly to the mixture at 0° C. Afteraddition, the reaction mixture was stirred at r.t. for 2 hour. BF₃.Et₂O(10.4 ml) was then added slowly to the mixture at 0° C. After completionof the addition, the reaction mixture was stirred at r.t. for 30 min.10% NaOH solution was added slowly till the reaction mixture becomesbasic and then extracted with EtOAC. The organic was washed with brine,dried over Na₂SO₄ and concentrated. The crude product was purified bysilica gel (60-120) column chromatography using 35% EtOAC/pet ether aseluent. Yield: 2.5 g (38%). ¹H NMR (400 MHz, CDCl₃): δ 7.32 (m, 2H),6.10 (s, 1H), 0.98-0.95 (m, 2H), 0.83-0.78 (m, 2H). LCMS: (ES+)m/z=123.7 (M)⁺

Column: ATLANTS T3(2.1×50 mm) 3 micron

-   -   Mphase A: 10 mM NH₄COOH IN 98% H₂O, 2% MeCN    -   Mphase B: 10 mM NH₄COOH IN 2% H₂O, 98% MeCN    -   Flow: 0.8 ML/Min

Time % A % B 0.0 100.0 0 6 0.0 100.0 7.0 0.0 100.0

-   -   RT min: 1.65, wavelength: 220 nm

tert-butyl 1-(furan-3-yl)cyclopropylcarbamate

A solution of Boc anhydride (4.9 g, 22.47 mmol, 1.2 eq) and1-(furan-3-yl)cyclopropanamine (2.3 g, 18.69 mmol, 1.0 eq) in THF (25ml) was stirred at 0° C., and the stirring was continued at r.t.overnight. The reaction mixture was concentrated, and the crude productwas purified by silica gel (60-120) column chromatography using 5%EtOAC/Pet ether as an eluent. Yield: 2.5 g (60%). ¹H NMR (400 MHz,CDCl₃): δ 7.30 (d, J=3.2, 1H), 7.26 (d, J=3.2, 1H), 6.16 (s, 1H), 5.17(bs, 1H), 1.44 (s, 9H), 1.16 (s, 2H), 1.03 (s, 2H). LCMS (ES+) m/z=168.2(M−CMe₃+2H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm)

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100.0 0.0

-   -   RT min: 1.75, wavelength: 220 nm

tert-butyl 1-(pyridazin-4-yl)cyclopropylcarbamate

A solution of tert-butyl 1-(furan-3-yl)cyclopropylcarbamate (2.15 g,9.64 mmol, 1.0 eq), in acetone (86 ml) and water (86 ml) at r.t. waspurged with N₂ and cooled to −20° C. NaHCO₃ (1.62 g, 19.28 mmol, 2.0 eq)and N-bromosuccinimide (2.23 g, 12.52 mmol, 1.3 eq) were added to themixture at −20° C. and the stirring was continued at the sametemperature for 2 hr. To the reaction mixture at −20° C. was added THF(4.3 ml) and the temperature raised to 0° C. over 30 min. Acetone wasremoved from the reaction mixture with a stream of N₂, and to theresidue at 0° C. was added isopropanol (86 ml) followed by hydrazinehydrate (12.9 ml). The reaction mixture was stirred at r.t. overnight.Product formation was confirmed by LCMS. The solvent was evaporatedunder reduced pressure, and the residue diluted with water and thenextracted with EtOAC. The organic was washed with brine, dried overNa₂SO₄ and concentrated. The crude product was purified by silica gel(60-120) column chromatography using 4% MeOH/CHCl₃ as an eluent. Yield:1.3 g (57.5%). ¹H NMR (400 MHz, CDCl₃): δ 9.04 (d, J=5.6, 1H), 8.95 (d,J=2.8, 1H), 7.19 (s, 1H), 5.25 (bs, 1H), 1.42 (s, 9H), 1.25 (bs, 4H).LCMS: (ES+) m/z=236.2 (M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100 0

-   -   RT min: 1.18, wavelength: 220 nm

1-(pyridazin-4-yl)cyclopropanamine HCl salt

To a mixture of tert-butyl 1-(pyridazin-4-yl)cyclopropylcarbamate (0.100g, 0.425 mmol, 1.0 eq) in a solution of 4.0 M HCl in 1,4-dioxane (4.0ml) was stirred at r.t. for 5 hr. The reaction mixture was concentratedunder vacuum and dried HCl salt was taken to next step.

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-4-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.07 g, 0.173 mmol, 1.0 eq) and 1-(pyrimidin-4-yl)cyclopropanamineHCl (0.023 g, 0.173 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.087g, 0.861 mmol, 5.0 eq) and BOP reagent (0.114 g, 0.257 mmol, 1.5 eq).The reaction mixture was stirred at r.t. overnight. The reaction mixturewas diluted with water and extracted with EtOAc. The organic was driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby silica gel (60-120) column chromatography using 3% MeOH/CHCl₃ aseluent and further purified by prep HPLC. Yield: 0.040 g (44.45%). 1HNMR (400 MHz, CD₃OD): δ 9.03 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.8 Hz, 1H),8.04-7.94 (m, 2H), 7.91-7.83 (m, 2H), 7.72-7.64 (m, 2H), 7.57-7.45 (m,2H), 7.43-7.37 (m, 1H), 7.34-7.24 (m, 2H), 2.96 (s, 3H), 2.37 (s, 3H),1.90-1.81 (m, 2H), 1.57-1.49 (m, 2H). ¹⁹F NMR (376.51 MHz, CD₃OD): δ−78.35 (TFA), −113.31. LCMS: (ES+) m/z=521.2 (M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100 0

-   -   RT min: 1.82, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 24 10 31 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.43    -   Wavelength: 220 nm, RT min: 16.43

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: 0.05% TFA in water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:water (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 15.265

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.096 g, 0.221 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamineHCl (0.03 g, 0.221 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.12 g,1.188 mmol, 5.0 eq) and BOP reagent (0.146 g, 0.330 mmol, 1.5 eq). Thereaction mixture was stirred as RT overnight. The reaction mixture wasdiluted with water, extracted with EtOAc. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel (60-120) column chromatography using3% MeOH/CHCl₃ as eluent. Yield: 0.070 g (57.33%). ¹H NMR (400 MHz,CD₃OD): δ 8.99 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.99-7.93 (m,2H), 7.79 (s, 1H), 7.69-7.54 (m, 3H), 7.39-7.23 (m, 3H), 7.16 (s, 1H),4.08 (s, 3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.85-1.82 (m, 2H), 1.61-1.49(m, 2H). LCMS: (ES+) m/z=551.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.91, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 25 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 17.55    -   Wavelength: 220 nm, RT min: 17.55

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: 0.05% TFA in water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:water (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.06    -   Wavelength: 220 nm, RT min: 16.06

2-(4-Fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridazin-4-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.075 g, 0.186 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamineHCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.094g, 0.93 mmol, 5.0 eq) and BOP reagent (0.123 g, 0.278 mmol, 1.5 eq). Thereaction mixture was stirred at RT overnight. The reaction mixture wasdiluted with water, extracted with EtOAc. the The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by silica gel (60-120) column chromatographyusing 4% MeOH/CHCl₃ as eluent, and further purified the product by prepHPLC. Yield: 0.050 g (52.00%). 1H NMR (400 MHz, CD₃OD): δ 9.44 (s, 1H),9.15 (d, 1H), 9.11 (s, 1H), 8.02-7.94 (m, 2H), 7.86 (dd, J=2.3, 4.3 Hz,2H), 7.73 (br s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H),7.48 (d, J=8.8 Hz, 1H), 7.40 (dd, J=1.8, 8.5 Hz, 1H), 7.29 (t, J=8.9 Hz,2H), 2.96 (s, 3H), 2.37 (s, 3 H), 1.71 (s, 4H). ¹⁹F NMR (376.51 MHz,CD₃OD): δ −78.16 (TFA), −113.29 LCMS: (ES+) m/z=521.2 (M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100 0

-   -   RT min: 1.71, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 26 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 14.37    -   Wavelength: 220 nm, RT min: 14.37

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: 0.05% TFA in water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:water (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 14.05    -   Wavelength: 220 nm, RT min: 14.05

2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridazin-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.080 g, 0.184 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamineHCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.093g, 0.920 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq).The reaction mixture was to stirred at RT overnight. The reactionmixture was diluted with water, extracted with EtOAc. The organic layerwas washed with brine and dried over Na₂SO₄, filtered and concentrated.The crude product was purified by silica gel (60-120) columnchromatography using 4% MeOH/CHCl₃ as eluent and further purified byprep HPLC. Yield: 0.053 g (52.42%). ¹H NMR (400 MHz, CD₃OD): δ 9.21-9.16(m, 2H), 8.01-7.94 (m, 2H), 7.81 (br. s., 1H), 7.77 (s, 1H), 7.66 (s,1H), 7.60 (s, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.17(s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.38 (s, 3H), 1.75 (s, 4H). ¹⁹F NMR(376.51 MHz, CD₃OD): δ −77.43 (TFA), −112.62. LCMS: (ES+) m/z=551.2(M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.84, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 14.99    -   Wavelength: 220 nm, RT min: 14.99

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: 0.05% TFA in water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:water (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 14.07    -   Wavelength: 220 nm, RT min: 14.07

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyridazin-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.080 g, 0.177 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamineHCl (0.024 g, 0.177 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.090g, 0.89 mmol, 5.0 eq) and BOP reagent (0.117 g, 0.264 mmol, 1.5 eq). Thereaction mixture was stirred at RT overnight. The reaction mixture wasdiluted with water, extracted with EtOAc. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by silica gel (60-120) column chromatography using4% MeOH/CHCl₃ as eluent. Yield: 0.060 g (60.0%). ¹H NMR (400 MHz,CD₃OD): δ 9.08 (m, 1H), 9.05 (d, J=1.0, 5.8 Hz, 1H), 7.97-7.93 (m, 2H),7.72 (s., 1H), 7.54 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H),7.19 (s, 1H), 4.10 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.63 (s, 4H).¹⁹F NMR (376.57 MHz, CD₃OD): δ −112.33, −122.75. LCMS: (ES+) m/z=569.2(M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100 0

-   -   RT min: 1.74, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.33    -   Wavelength: 220 nm, RT min: 9.33

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.21    -   Wavelength: 220 nm, RT min: 9.21

4-Fluoro-2-(4-fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(pyrimidin-4-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide

To a mixture of5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoicacid (0.080 g, 0.185 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamineHCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF and at 0° C. was added TEA(0.094 g, 0.930 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5eq). The reaction mixture was warmed to RT, and stirring was continuedat RT overnight. The reaction mixture was diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby prep HPLC. Yield: 0.058 g (58.0%). ¹H NMR (400 MHz, CD₃OD): δ 9.03(s, 1H), 8.64 (d, J=1.4 Hz, 1H), 7.97-7.79 (m., 2H), 7.76 (s, 1H), 7.65(d, J=5.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s,1H), 4.09 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.88-1.85 (m, 2H),1.55-1.52 (m, 2H). ¹⁹F NMR (376.57 MHz, CD₃OD): δ −77.58 (TFA), −112.32,−122.76. LCMS: (ES+) m/z=569.2 (M+H)⁺

Column-Ascentis Express C18 (5×2.1 mm-2.7 μm)

-   -   Mphase A: 2% MeCN-98% H₂O-10 mM NH₄COOH    -   Mphase B: 98% MeCN-2% H₂O-10 mM NH₄COOH    -   Flow: 1 ML/Min

Time % A % B 0.0 100.0 0 1.5 0.0 100.0 3.2 0.0 100.0

-   -   RT min: 1.89, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 16.78    -   Wavelength: 220 nm, RT min: 16.78

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: 0.05% TFA in water:MeCN (95:5)    -   Mobile Phase B: 0.05% TFA in MeCN:water (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 25 100 30 100

-   -   Wavelength: 254 nm, RT min: 15.08    -   Wavelength: 220 nm, RT min: 15.08

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-4-yl)-cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamineHCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq).The reaction mixture was stirred at RT overnight. The reaction mixturewas diluted with water and extracted with EtOAc. the organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by preparative HPLC. Yield: 0.035 g (57.37%).¹H NMR (400 MHz, CD₃OD): δ 9.00 (d, J=1.2 Hz, 1H), 8.60 (d, J=5.6 Hz,1H), 7.98-7.90 (m and dd, 3H), 7.85 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.51-7.49 (two overlapping d, 2H), 7.35-7.28 (m, 3H), 2.96 (s,3H), 2.30 (s, 3 H), 1.84-1.81 (m, 2H), 1.52-1.49 (m, 2H). ¹⁹F NMR(376.57 MHz, CD₃OD): δ −76.94 (TFA), −112.22, −122.76 LCMS: (ES+)m/z=539.2 (M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100 0

-   -   RT min: 1.78, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: meCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 10.02    -   Wavelength: 220 nm, RT min: 10.02

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.53    -   Wavelength: 220 nm, RT min: 9.53

4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyridazin-4-yl)-cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamide

To a mixture of3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoicacid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamineHCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq).The reaction mixture was stirred at RT. overnight. The reaction mixturewas diluted with water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by preparative HPLC. Yield: 0.030 g (50.0%).¹H NMR (400 MHz, CDCl₃): δ 9.03 (d, J=5.6 Hz, 1H), 8.98 (m, 1H),8.01-7.98 (m., 2H), 7.81-7.78 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=2 Hz,1H), 7.44 (d, J=8.4, 2H), 7.28-7.26 (dd, 1H), 7.23-7.18 (m, 3H), 7.08(s, 1H), 6.20 (bs, 1H), 3.04 (d, J=5.2 Hz, 3H), 2.29 (s, 3H), 1.61-1.54(m, 4H). ¹⁹F NMR (376.57 MHz, CDCl₃): δ −109.53, −119.52. LCMS: (ES+)m/z=539.2 (M+H)⁺

Column: purospher@star RP-18 (4×55)mm, 3 μm

-   -   Mphase A: 20 mM NH₄OAc IN 90% H₂O, 10% MeCN    -   Mphase B: 20 mM NH₄OAc IN 10% H₂O, 90% MeCN    -   Flow: 2.5 ML/Min

Time % A % B 0.0 100.0 0 2 0.0 100.0 2.5 0.0 100.0 3 100 0

-   -   RT min: 1.68, wavelength: 220 nm

HPLC Method: SUNFIRE C18 (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 9.00    -   Wavelength: 220 nm, RT min: 9.00

HPLC Method: XBridege phenyl (4.6×150)mm, 3.5 micron

-   -   Buffer: 0.05% TFA in water pH 2.5    -   Mobile Phase A: Buffer:MeCN (95:5)    -   Mobile Phase B: MeCN:Buffer (95:5)    -   FLOW: 1 ml/min

Time B % 0 10 12 100 15 100

-   -   Wavelength: 254 nm, RT min: 8.89    -   Wavelength: 220 nm, RT min: 8.89

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

1. A composition comprising the compound4-Fluoro-2-(4-fluorophenyl)-N-methyl-5-(2-methyl-5-(1-(pyrimidin-2-yl)cyclopropylcarbamoyl)phenyl)benzofuran-3-carboxamideor a pharmaceutically acceptable salt thereof, and at least one compoundhaving anti-HCV activity effective to inhibit the function of a targetselected from the group consisting of HCV metalloprotease, HCV serineprotease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCVassembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analogfor the treatment of an HCV infection.